鱼精蛋白剂量——ACT反应曲线在对抗肝素中的优越性

我院自1980年建立激活全血凝固时间(ACT)监测方法以来,一直用肝素剂量-ACT反应曲线作为指导体外循环肝素用量以及鱼精蛋白拮抗肝素的用量指标。但发现用此法计算的鱼精蛋白量输入后ACT值常离基础值较远。1983年Gandhi在临床上进行了鱼精     

体外循环术中监测激活全血凝固时间的初步体会

在体外循环心内直视手术中,按常规或经验给予肝素和鱼精蛋白的方法,有时因用药量不准确,易给患者带来不良影响。术中监测激活全血凝固时间(简称ACT)指导肝素和鱼精蛋白用量,具有减少术后渗血,防止鱼精蛋白过量等优点。1983～1984年我们对14例行体外循环心内直视手术的患者应用国产Q/HG硅藻土测定ACT,并以37例     

体外循环术中自体血回收对血液成分及凝血功能的影响

目的观察体外循环术中不同自体血回收方式对患者血液成分及凝血功能的影响。方法随机将60例体外循环下心脏手术的成人患者分为A、B两组,均为30例。A组为观察组,全部术野出血用自体血液回收机离心洗涤后于手术结束前回输体内。B组为对照组,不采用自体血液回收机,将肝素化后的术野出血直接吸回体外循环系统停机前回输体内,鱼精蛋白拮抗后机器余血打入输血袋,于手术结束前静脉回输。对两组患者麻醉前、体外循环中及术毕静脉血进行血常规及凝血四项指标的测定,记录停机后两组激活凝血时间（ACT）及术后24h内胸腔引流量和输注异体血用量,并对以上观察结果进行比较分析。结果①观察组患者术后24h内胸腔引流量及异体血用量明显少于对照组,差异有统计学意义（P〈0．05）。②与术前相比,两组患者血红蛋白（Hb）、红细胞比容（Hct）和血小板（PLT）均明显下降,凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）和凝血酶时间（TT）明显延长,但两组间比较差异无统计学意义。③术毕观察组Hb和Hct值较体外循环中明显回升,且与对照组相比差异有统计学意义,但仍略低于术前。④两组术毕PLT、PT、APTT和TT均明显低于术前,但仍在正常范围内,两组间差异无统计学意义。结论体外循环期间自体血回收对患者血液成分及凝血功能的影响不明显,是一种有效的血液保护方法。     

围体外循环期间活化凝血时间和激活部分凝血活酶时间与未分段肝素浓度相关性分析的初步研究

目的:研究体外循环手术前后,活化凝血时间(ACT)与激活部分凝血活酶时间(APTT)指标,在反应患者体内肝素实际浓度方面的价值。方法:采用观察性研究,选取因心脏瓣膜疾病需要进行体外循环下瓣膜置换手术的患者39例,于手术过程中和术后24小时内间断抽取血样进行ACT及APTT监测,并保存血浆进行活化凝血因子抗FIIa因子及抗F_(Xa)因子定量检测,作为肝素实际浓度的指标。结果:在体外循环手术过程中全身肝素化,体内肝素浓度与ACT呈明显正相关(F_(Ⅱa)因子r=0.397,P<0.001;F_(Xa)因子r=0.461,P<0.001),停止体外循环后中和肝素,体内肝素浓度与ACT无相关(F_(Ⅱa)因子r=0.242,P=0.057;F_(Xa)因子r=0.300,P<0.001),与APTT正相关(F_(Ⅱa)因子r=0.397,P=0.008;F_(Xa)因子r=0.391,P=0.010)。结论:体外循环过程中ACT是良好的体内肝素浓度评价指标,肝素中和后APTT及ACT都不能完全准确反应体内肝素浓度,APTT与实际肝素浓度的相关性要优于ACT。     

体外循环手术中鱼精蛋白不良反应26例分析

体外循环手术中鱼精蛋白中和肝素是一项重要措施 ,但其不良反应也时有发生。 1990年 12月～ 2 0 0 0年 12月 ,我院行体外循环手术 35 0例 ,其中发生鱼精蛋白不良反应 2 6例。现报告如下。临床资料 :本组 2 6例中 ,男 9例 ,女 17例。年龄 4～ 2 7岁 ,平均 34岁 ;体重 2 0～ 75 kg,平均 2 3.5 kg。瓣膜病 3例 ,先天性心脏病 2 0例 ,冠心病、心脏粘液瘤各 1例。全组患者均在低温体外循环下完成手术。术中应用国产肝素抗凝 (3mg/kg) ,保持激活的全血凝固时间 (ACT)为 480～ 6 0 0 S;停机后用鱼精蛋白经主动脉根部或中心静脉缓慢推注中和肝素。…     

体外循环抗凝失误与意外七例教训

体外循环(CPB)下抗凝不足会耗竭凝血因子而导致CPB后凝血病,而肝素过量却会增加术后渗血。我院自1980年起,便常规用激活全血凝固时间(ACT)监测肝素抗凝与鱼精蛋白拮抗,至今已积累9000余例。但目前发现,如注用肝素后不监测ACT,或不获ACT报告结果便开始CPB或紧急转机,会给病人带     

体外循环中全血激活凝血时间(ACT)的监测

我院自1987年采用全血激活凝血时间(ACT)监测来指导体外循环病人肝素抗凝和鱼精蛋白中和100例,取得了良好的效果。一、一般资料:100例中先心病70例,其中紫绀型10例,非紫绀型60例;后天性心脏     

国产比伐卢定对急性冠状动脉综合征患者介入术中凝血功能的影响

目的:探讨国产注射用比伐卢定和普通肝素在急性冠状动脉综合征患者冠状动脉介入术中对凝血功能的影响。方法:入选95例择期行PCI的急性冠状动脉综合征患者,随机分为肝素组(n=49)和比伐卢定组(n=46),其中肝素组脱落3例,比伐卢定组脱落5例,比伐卢定组和肝素组各剔除6例。根据分组不同术中分别采用国产注射用比伐卢定或肝素抗凝。分别在用药前、用药后5 min、首次用药后30 min、停药后1 h及6 h检测活化凝血时间(ACT)。比较首次给药5min后和30min后的ACT达标率。结果:2组患者基线资料具有可比性,术前凝血指标差异无统计学意义(P>0.05),比伐卢定组和肝素组用药后ACT值迅速升高,2组5min和30minACT达标率相当,差异无统计学意义(P>0.05)。用药结束后比伐卢定组ACT值下降迅速,用药结束后1hACT值较肝素组显著降低,2组之间差异有统计学意义(P<0.05)。用药结束后6 h,2组ACT值下降至与基线相当,2组之间差异无统计学意义(P>0.05)。肝素组用药后5 min、30 min和1 h,ACT值的标准差均大于比伐卢定组。结论:与常规肝素抗凝相比,比伐卢定在PCI术中可以获得更稳定的抗凝效果,其作为抗凝剂用于PCI术中安全有效。     

冠状动脉再狭窄家猪模型中普通肝素用量的探讨

目的 评价低、中度肝素化在冠状动脉再狭窄家猪模型中的应用效果,探讨该模型合理的普通肝素用量.方法 根据普通肝素用量将24只健康家猪随机分为低度肝素化组(100 U/kg)和中度肝素化组(150 U/kg)各12头.分别测定基础促凝时间(ACT)和静脉注射肝素后不同时间点ACT.比较两组的抗凝效果,术后压迫止血情况及术中、术后24 h的安全性.采用SPSS 10.0进行统计学分析.结果 中度肝素化组和低度肝素化组在静脉推注普通肝素后5 min ACT达到峰值(245.3±93.64 s对241.0±37.29 s,P=0.824),20 min时两组维持较高ACT值(191.8±53.06 s对184.6±42.82 s,P=0.707).30 min时中度肝素化组ACT值(193.9±58.95 s)无显著变化,而低度肝素化组ACT值(154.0±28.20 s)明显回落,与前者相比,差异有统计学意义(P=0.005).中度肝素化组术后徒手压迫止血时间显著长于低度肝素化组(17.7±2.96 min对14.3±4.44 min,P=0.042).两组术中和术后24 h均未发生冠状动脉事件.结论 在家猪冠状动脉再狭窄模型中,若手术时间控制在20min内,则低度肝素化(100 U/kg)既可保证手术的安全性又可缩短压迫止血时间.     

体外循环时氧自由基产生与激活补体的关系

为了明确体外循环对补体的激活,肺内白细胞旷置和产生氧自由基的关系,作者选择15例体外循环下实施冠状动脉搭桥术的病人进行观察。此15例病人左室功能良好,无肺疾病,也无过敏反应史.术前除贫血外,均用晶体液补充。插管前注肝素350微克/公斤,体外循环后慢注鱼精蛋白(1.3纳克/100单位肝素)中和肝素。按计划采动脉血测定C_3~(?)a,C_4a,C_5a和H_2O_2.体外循环结束后从左房、右室取血进行血细胞计数和白细胞分类计数.用中性白细胞数的差值反映肺循环白细胞旷置. 结果:体外循环时C_3a从开始的387±42毫克/分升逐渐上升到结束时的943±91毫克/分升(P<0001),体外循环之后继发性上升高达1807±150毫克/分升(P<0.001)可能与注鱼精蛋白有关.体外循环时C_4a不高,提示传统途径来被激活.注鱼精蛋白后C_4a299从±145毫克/分升升高至975±120毫克/分升(P<0.001).与此同时均未检出C_5a.体外循环后白细胞总数明显上升(P<0.05),     

Clinical effects of different protamine doses after cardiopulmonary bypass

The optimal dose of protamine needed to reverse the anticoagulant effect of heparin after cardiopulmonary bypass is still not known. In this retrospective cohort study, we investigated 3 different dose regimes in 300 patients undergoing coronary artery bypass grafting. Group A patients (n = 100) were given protamine in the ratio of 1.3 mg to 1 mg heparin, group B patients (n = 100) were given 0.75 mg protamine to 1 mg heparin, and group C patients (n = 100) were given protamine in fractionated doses of 1 mg + 0.15 mg + 0.15 mg to 1 mg heparin. The groups were comparable in all major clinical and operative variables. The heparin dose was almost identical in the groups. The rate of red cell transfusion was significantly higher in group B than in the other groups. A similar but nonsignificant trend was observed in the incidence of resternotomy for postoperative bleeding, mediastinal drainage, and postoperative hemoglobin loss. The study demonstrates that a single bolus dose of 1.3 mg protamine to 1 mg heparin is safe and efficient for neutralizing heparin after cardiopulmonary bypass.     

Bivalirudin, blood loss, and graft patency in coronary artery bypass surgery

A safe and effective alternative is needed for patients in whom unfractionated heparin (UFH) or protamine is contraindicated (e.g., those with heparin-induced thrombocytopenia or allergy to protamine). Furthermore, choice of anticoagulant may influence graft patency in coronary surgery and may therefore be important even when there is no contraindication to UFH. Direct thrombin inhibitors have several potential advantages over UFH, demonstrated in acute coronary syndromes. However, there are also potential difficulties with their use related to lack of reversal agents and paucity of clinical experience in monitoring their anticoagulant activity at the levels required for cardiac surgery with cardiopulmonary bypass (CPB). In the first prospective randomized trial of an alternative to heparin in cardiac surgery, we compared bivalirudin (a short-acting direct thrombin inhibitor) with UFH in 100 patients undergoing off-pump coronary artery bypass (OPCAB) surgery. Blood loss for the 12 hours following study drug initiation in the bivalirudin group was not significantly greater than in the heparin group. Median graft flow was significantly higher in the bivalirudin group. We concluded that anticoagulation for OPCAB surgery with bivalirudin was feasible without a clinically important increase in perioperative blood loss. A larger study is needed to investigate the impact of improved graft patency on other clinical outcomes after cardiac surgery.     

Protamine dosage based on two titrations reduces blood loss after valve replacement surgery: a prospective, double-blinded, randomized study

Background

Postoperative hemorrhage following cardiopulmonary bypass in heart valve replacement patients may be caused by a mismatch of protamine and heparin. We hypothesized that a 2-titration-guided protamine dose would reduce protamine-heparin mismatch and bleeding in those patients.

Methods

Patients scheduled for elective cardiac valve replacement surgery (N = 60) were randomly divided into 3 groups. All patients received 2 titrations: the first at termination of cardiopulmonary bypass and the second at 5 minutes after the initial dose of protamine. In the control group, the initial protamine dose was based on the heparin dose received; the supplemental protamine dose was empirically determined. In the single-titration group, the initial dose was based on the first titration, while supplemental dose was empirically determined. In the 2-titration group, both initial and supplemental doses were based on titrations. Bleeding volumes were recorded from the time of first protamine dose to 24 hours after surgery.

Results

Most patients needed supplemental protamine according to second titrations. In the 2-titration group, 12 patients received supplemental protamine, whereas only 1 patient in the single-titration group and 6 in the control group received supplemental protamine (P = 0.003). The blood loss was significantly less in the 2-titration group (526 ± 131 mL) than in the control group (730 ± 385 mL; P = 0.019).

Conclusions

A higher dosage of protamine based on 2 titrations reduced blood loss after surgery, supporting the hypothesis that inadequate dosage of protamine contributes to hemorrhage after valve replacement surgery.     

Factor VIIa-Antithrombin complexes during cardiac surgery using cardiopulmonary bypass

Antithrombin inhibits VIIa when bound to cellular tissue factor in the presence of heparin. VIIa concentrations increase within the surgical field during cardiopulmonary bypass surgery but decrease when measured in the patient. Using a new ELISA (Stago, Reading, UK), we measured VIIa-antithrombin complexes in patients undergoing cardiopulmonary bypass to determine whether antithrombin plays a physiological role in VIIa inhibition during cardiac surgery. Samples were taken from 13 adult patients undergoing cardiac surgery with cardiopulmonary bypass at the following time points: presurgery, postheparin, 20 min intervals during cardiopulmonary bypass and postprotamine. The presurgery concentrations of VIIa-antithrombin complexes were median of 52.7pm, and these rose postheparin bolus to a median of 110pM that was maintained throughout cardiopulmonary bypass and postprotamine administration. There is an approximate twofold increase in measurable VIIa-antithrombin complexes in patients undergoing cardiac surgery, which is apparent after heparin administration. Antithrombin appears to play an active role in VIIa inhibition during cardiac surgery.     

Low molecular weight heparin in extracorporeal circulation. 1st clinical applications

The haemorrhagic complications inherent to the use of heparin during cardiac surgery led us, after a pilot experimental study, to try out a low molecular weight heparin (LMWH), PK 10169, which has weaker haemorrhagic effects in vitro. Our initial experience was confined to 23 patients with differing pathologies, undergoing cardiopulmonary bypass lasting 30 to 165 minutes. The modes of injection of YK 10169 varied according to the results, especially with respect to the limitation of peaks of anti-Xa activity; 8 patients were given one bolus intravenous injection, 9 were given a bolus injection and a continuous infusion, and 6 were only given the continuous infusion. Biological monitoring of anticoagulation was based on anti-Xa activity. Analysis of the biological results showed that the principal feature was the partial correction, and occasionally the non-correction of anti-Xa activity by protamine sulphate, with no correlation between this anti-Xa activity and postoperative bleeding. The authors report cases of severe postoperative bleeding despite the supposed theoretical and experimental weakly haemorrhagic properties of LMWH, and also discuss the inefficacy of protamine sulphate. The indications for LMWH for cardiopulmonary bypass which were retained, were the rare cases of heparin-induced thrombocytopaenia. In conclusion, it is possible to use LMWH during cardiac surgery but we do not advise using it routinely as its theoretical advantages are not confirmed in practice.     

心脏直视手术中鱼精蛋白过敏性休克的救治

回顾体外循环后鱼精蛋白拮抗肝素期间发生过敏性休克、心搏骤停2例，均属严重肺血管收缩型毒性反应。结合文献复习，作者认为：严重的鱼精蛋白过敏反应发病急骤，临床表现严重。立即二次转机辅助循环，应用副肾素、抗组织胺类药物和大剂量激素，及时补足血容量是主要抢救措施。而鱼精蛋白毒性反应发生与否与有无鱼类食物过敏史、注射途径、是否二次使用鱼精蛋白、鱼精蛋白皮试是否阴性均无相关性。缓慢注射（＞3min）可防止快速给药反应型毒性反应的发生，但无助于防止严重肺血管收缩型毒性反应的发生。     

Hemostatic effects of low-dose protamine following cardiopulmonary bypass

Twenty-eight patients undergoing cardiac surgery were prospectively studied and were assigned to two groups. The patients received 0.8- (Group L) or 2.0-fold (Group H) dose of protamine for the neutralization after cardiopulmonary bypass (CPB) which was determined by Hepcon HMS(R) assay system in which the reagent chamber containing the concentration of protamine that completely neutralized the heparin had the shortest clotting time. Mean dose of protamine was 1.60 +/- 0.50 mg kg(-1) in Group L, and 3.56 +/- 1.48 mg kg(-1), respectively. Activated clotting times (ACT) were comparable between the two groups through this study period. In Group H, platelet counts significantly decreased to 69% of that before protamine administration, and plasma platelet factor 4 level significantly increased to approximate 2-fold of that before protamine administration just after protamine administration, respectively. However, these phenomena were not observed in Group L. In addition, these hemostatic changes occurred transiently just after protamine administration. We conclude that the low-dose protamine may prevent transient platelet depletion following CPB. Low-dose protamine can neutralize anticoagulation effect of heparin sufficiently and may mitigate protamine-induced platelet dysfunction.     

Successful cardiopulmonary bypass in diabetics with anaphylactoid reactions to protamine.

Two insulin dependent diabetics with previous anaphylactic like (anaphylactoid) reactions to protamine underwent successful cardiopulmonary bypass for coronary artery surgery. Platelet concentrates instead of protamine were used to neutralise their systemic heparinisation. In both cases the anaphylactoid reactions first became apparent after administration of protamine sulphate at the end of cardiac catheterisation. These cases show that adverse reactions to protamine need not be a contraindication to cardiopulmonary bypass and cardiac surgery and emphasise that this condition should be considered in all patients with a history of previous protamine exposure or one which may be associated with anaphylactoid reactions to protamine.     

Reheparinisation requirements after cardiopulmonary bypass in patients treated with aprotinin.

OBJECTIVE--To determine reheparinisation requirements following protamine neutralisation after the discontinuation of cardiopulmonary bypass in a group of patients receiving "low dose" aprotinin compared with a control group. DESIGN--Randomised, placebo controlled study. SETTING--Regional cardiothoracic unit within a district general hospital. PATIENTS--20 patients were consecutively allocated to one of two groups. All patients had a primary elective aortocoronary bypass operation using standard anaesthetic techniques and no patient was withdrawn from the study. INTERVENTIONS--Aprotinin group patients (n = 9) received aprotinin (1 x 10(6) kallikrein inactivator units (KIU)) as an intravenous bolus after the induction of anaesthesia, and 1 x 10(6) KIU was added to the pump prime. Control group patients (n = 11) received 0.9% saline placebo. MAIN OUTCOME MEASURES--Activated clotting time (ACT), heparin concentration, and heparin dose response (HDR) measured before, during, and after bypass. The HDR is an accurate method to determine the patients' in vitro response to heparin and is used to predict the dose of heparin required to attain an ACT of 400 seconds. RESULTS--Activated clotting times were similar in the two groups for the duration of the study. Heparin concentrations were zero in all patients before heparin administration and after protamine neutralisation. During bypass there was no difference between the groups. The median heparin dose response was the same in the two groups before the administration of heparin, but after the neutralisation of heparin with protamine after the discontinuation of bypass the HDR was significantly higher in the aprotinin group for up to one hour (median of 2.9 IU/ml v 1.25 in the control group at 10 minutes after protamine neutralisation, P < 0.01; 2.5 v 1.45 at 30 minutes, P < 0.05; and 2.9 v 1.6 at one hour, P < 0.001). CONCLUSION--Heparin requirements were nearly doubled in patients treated with aprotinin, who required reheparinisation for up to one hour after protamine. This relative "heparin resistance" cannot be explained by the presence of excessive protamine. Aprotinin may be a substrate for the N-carboxypeptidase that destroys protamine, thus indirectly enhancing and prolonging the activity of protamine.     

Recombinant platelet factor 4 for heparin neutralization

Protamine sulfate has been used for many years to reverse the effects of unfractionated heparin, but it can cause hemodynamic changes and other serious side effects. Platelet factor 4 (PF4) is a naturally occurring protein synthesized in megakaryocytes and eventually stored in the alpha granules of platelets for later release. Although the complete physiologic role of PF4 is unknown, it is highly effective for the neutralization of heparin anticoagulation. Several preliminary animal studies and trials using blood obtained from cardiopulmonary bypass circuits suggested recombinant PF4 (rPF4) would be an effective alternative to protamine. In the first open-label, phase 1 human study, patients received rPF4 in doses of 0.5, 1.0, 2.5, or 5.0 mg/kg over 3 minutes to reverse heparin anticoagulation after diagnostic cardiac catheterization. There were no important hemodynamic changes and the rPF4 was highly effective in neutralizing heparin. Serial measurements of rPF4 levels showed a monophasic elimination pattern with a serum half-life of 25.5 +/- 13.5 minutes that was independent of dose administered. A randomized and blinded trial comparing rPF4 to protamine confirmed the safety and effectiveness of rPF4. Although rPF4 was initially being evaluated as a clinical alternative to protamine, it is not currently being developed for general clinical use.