How Do We Treat Arteriovenous Malformations (Tips and Tricks)?我们应该如何治疗动静脉畸形(技巧和绝招)?Young Soo Do, MD, Kwang-Bo Park, MD, and Sung Ki Cho, MD翻译:李明省(郑州大学第一附属医院神经介入科)Ethanol embolization is sufficient to eliminate or improve symptoms of arteriovenous malformations (AVMs) in a high percentage of patients, but with substantial risk of minor and major complications. Inadvertent embolization must be avoided by superselective catheterization or direct puncture of the nidus. According to the angiographic morphology of the nidus, AVMs of the trunk and extremities can be classified into four types: type I (arterio-venous fistulae), type II (arteriolo-venous fistulae), type IIIa (arteriolo-venulous fistulae without dilation of the fistula), and type IIIb (arteriolo-venulous fistulae with dilation of the fistula). The described angiographic classification provides considerable information concerning the characteristics of AVMs in the body and extremities, the optimal therapeutic approach, and the likely therapeutic outcome. Tech Vasc Interventional Rad 10:291-298 2007 Elsevier Inc. All rights reserved. KEYWORDS: arteriovenous malformation, ethanol, embolization, angiography无水乙醇栓塞能够有效消除或减轻大部分动静脉畸形患者的症状,但是或多或少都有一些并发症的发生。超选择栓塞和直接经皮穿刺畸形血管巢应该取代非超选择供养动脉无水乙醇注射,根据血管造影的形态学躯干和肢体的动静脉畸形可以分为四个类型:I型、主干动静脉瘘,II型、小动脉-静脉瘘,IIIa型、小动脉-小静脉瘘(不伴随瘘口扩张),IIIb、小动脉-小静脉瘘(伴随瘘口扩张),基于血管造影的分类系统能够为躯干和肢体血管畸形的治疗方法的选择和可能的预后判断提供相当多的参考信息。【关键词】动静脉畸形,无水乙醇,栓塞,血管造影Congenital arteriovenous malformations (AVMs) are a major challenge in medical practice, which are often associated with serious symptoms such as heart failure, neuropathy, pain, and bleeding. Embolotherapy has been a primary mode of treatment for the management of AVMs with improvements in catheter systems and selective techniques, which can be achieved through the transarterial, transvenous, or direct puncture approaches.先天性动静脉畸形在临床中极具挑战,常常伴随心衰、神经病变、疼痛和出血,随着导管系统的改进和入路的多样化,硬化治疗已经成为动静脉畸形的主要治疗模式,我们能够通过动脉、静脉、甚至经皮穿刺到达病灶进行硬化栓塞治疗。Despite the importance of angiography, most reports have traditionally described the angiographic features of AVMs in terms of feeding arteries, the complex network of arteriovenous shunts (referred to as the nidus), and draining veins. However, AVMs are so diverse and diffuse in nature that such descriptions are too broad to accurately represent the individualcharacteristics of an AVM. Furthermore, such descriptions have limitations in terms of aiding therapeutic decision making by interventional radiologists and in terms of the exchange of angiographic data between therapeutic teams.血管造影是血管畸形分类的极为重要依据,大多数文献仍从供养动脉、瘤巢和引流静脉三个方面情况来描述动静脉畸形。然而动静脉畸形在本质上又千差万别,现有的分类系统太过于宽泛,不能够精准地描述所有个例的特点。此外,这种分类系统在放射介入医生制定治疗计划和造影数据交流方面存在局限。Recently, to help the therapeutic decision making for performing embolotherapy, we have proposed four prototypes of peripheral AVMs based on the angiographic morphology of the nidus. In this article, we described therapeutic results and approaches to the ethanol embolization of AVMs according to a newly proposed angiographic classification of AVMs of the body and extremities.近来,为辅助栓塞治疗方案的制定,基于瘤巢血管造影形态学我们提出4种类型的分类方法原型,本文里我们将基于新的分类系统介绍无水乙醇栓塞治疗躯干和肢体动静脉畸形的目标和结果。Techniques and Methods Patient Selection Criteria All patients referred to our hospital had serious problems. These included severe pain, a pulsating growing mass, ulceration at the lesion site, bleeding at the ulcerated skin, vaginal bleeding, dysmenorrhea, bone overgrowth at the lesion site, symptoms or signs of congestive heart failure consisting of dyspnea on exertion and cardiomegaly, ischemic symptoms at the extremities of the distal part of AVMs as a result of a steal effect through a high-flow shunt, or their combinations. The patients usually had more than one symptom and sign. Except severe infection associated with AVMs, the AVMs of extremity and trunk were treated by ethanol embolization.技术和方法患者选择标准所有入选患者均有严重临床症状,比如:严重的疼痛、搏动性生长的肿块、病变部位溃疡、溃疡皮肤的出血、阴道出血、痛经、病变部位骨过度生长,劳力性呼吸困难、心脏肥大等充血性心力衰竭症状,以及因AVM分流所致的远端肢体缺血症状或其合并症。入选患者常常不止出现一种症状,除AVM合并感染外,所有肢体和躯干AVM均接受无水乙醇硬化栓塞治疗。Diagnosis and Follow-up of AVMs The diagnoses of AVMs were made based on the clinical and imaging examinations. The lesion was first assessed by a physical examination. Multidetector computed tomography (MDCT) or magnetic resonance (MR) imaging besides the selective angiography should be performed to obtain the detailed anatomical and hemodynamic information of AVMs. MDCT or MR imaging are also good imaging modalities for the evaluation of residual lesions or recurrence after treatment.AVM的诊断和随访AVM需基于临床表现和影像检查综合得出诊断结论,影像检查之前需要进行详细的体格检查,血管造影之前需要完善多层螺旋CT检查或磁共振检查,以便了解畸形血管团的解剖和血流动力学信息,多层螺旋CT或磁共振检查还是评价残余病灶和复发病灶的良好手段。The Angiographic Classification of AVMs It is well known that the nidus of AVMs is fundamentally a conglomeration of arteriovenous fistulae. AVMs of the body and extremities can be classified into four types according to their angiographic morphologies (Fig. 1), as follows: type I (arterio-venous fistulae), when at most three separate arteries are shunted to a single draining vein; type II (arteriolo-venous fistulae), when multiple arterioles are shunted into a single draining vein; type III (arteriolo-venulous fistulae), when multiple shunts are located between the arterioles and venules. In this type, if the fistula unit of the nidus is observed as a blush or fine striation on angiography, it is subdivided into either; type IIIa (arteriolo-venulous fistulae with nondilated fistula), when the fistula unit of the nidus is observed as a complex vascular network; or type IIIb (arteriolo-venulous fistulae with dilated fistula). This classification can be regarded as a modification of the previous classification proposed by Houdart and coworkers, because they classified intracranial AVMs into three types based on the morphology of the nidus—arterio-venous, arteriolo-venulous, and arteriolo-venulous fistulae.AVM的血管造影分类方法从根本上讲,动静脉畸形的瘤巢实际上是包含小动脉-小静脉瘘的团块,根据血管造影形态学躯干和肢体AVM可以分成以下4种类型:I型、主干动静脉瘘(不超过3根单独的动脉分流到一根引流静脉);II型、小动脉-静脉瘘(多支<< span="">超过3支>小动脉分流到单支引流静脉);III型、小动脉-小静脉瘘,根据造影表现为“肿瘤”染色还是“线样征”又可再分为IIIa型和IIIb型,其中IIIa型、小动脉-小静脉瘘不伴随瘘口扩张,也就是瘤巢的瘘表现为复杂的血管网,IIIb型、小动脉-小静脉瘘伴随瘘口扩张。Houdart及其同事基于形态学将颅内AVM分为①瘤巢-动脉-静脉,②小动脉-小静脉和③小动脉-小静脉瘘,本分类方法可以看作是对Houdart及其同事分类方法的改进。图1.Type I (arterio-venous fistulae) AVMs: No more than three separate arteries shunt to the initial part of a single venous component.I型、主干型动静脉瘘:不超过3根单独动脉分流至单根静脉的起始部Type II (arteriolo-venous fistulae): Multiple arterioles shunt to the initial part of a single venous component, in which the arterial components show a plexiform appearance on angiography.II型、小动脉-静脉瘘:超过3根以上动脉瘘到单根静脉起始部,造影表现为网丛状的染色Type IIIa (arteriolo-venulous fistulae with nondilated fistula): Fine multiple shunts are present between arterioles and venules and appear as a blush or fine striation on angiography.IIIa型、不伴随瘘口扩张的小动脉-小静脉瘘,小动脉-小静脉之间多发细小瘘,造影表现为“肿瘤”染色或细条纹状血流Type IIIb (arteriolo-venulous fistulae with dilated fistula): Multiple shunts are present between arterioles and venules and appear as a complex vascular network on angiography.IIIb型、伴随瘘口扩张的小动脉-小静脉瘘:多发的小动脉和小静脉之间的直接分流,血管造影表现为复杂的的血管网络Procedures All of the ethanol embolization was performed under general anesthesia to control the pain, and Swan-Ganz and arterialline monitoring were performed in most patients to monitor the pulmonary artery pressure and arterial blood pressure. The objective of the staged ethanol embolization was to embolize not vascular feeders but all or part of the nidus until the complete resolution or improvement in the clinical symptoms and signs was achieved. In every session of embolotherapy, baseline selective and superselective angiographic studies were performed to determine the exact flow characteristics of the AVMs. After considering not only the angiographic features of the AVMs but also other factors such as important normal arterial or venous branches arising in very close proximity to a malformation and extreme arterial tortuosity or previous surgery precluding a successful transarterial catheterization, the approach of vascular access to attack the nidus itself was chosen. Transarterial, transvenous catheterization using a coaxial catheter, and/or percutaneous direct puncture was needed to reach the nidus being embolized. When focusing only on the morphology of the nidus, the type I and II AVMs can be embolized through any of the three approaches: transarterial, transvenous, or direct puncture approaches. The type IIIa AVMs can be treated only through a transarterial approach because they are too fine to be punctured directly. The type IIIb AVMs can be treated through either the transarterial or direct puncture approaches. In the type III AVMs, embolization through the transvenous approach is contraindicated because embolic materials introduced by a transvenous approach will not reach the shunts but block the venous drainage. Therefore, this will result in hypertension in the shunts and aggravation of AVMs if the arterial contribution is not disrupted. By the definition of this classification, the type II AVMs have multiple tortuous feeding arterioles and a large dilated venous component. Therefore, it is important to attack the venous component of the nidus through a direct puncture or transvenous approaches rather than through the transarterial approach. Also, a direct puncture and transvenous approach can avoid the risk of an inadvertent occlusion of the adjacent normal vessels by the transarterial approach. In the mixed type AVMs, the transarterial and direct puncture approaches of embolotherapy, which can treat both components of the AVMs simultaneously, are preferred.操作步骤所有无水乙醇硬化栓塞均在全麻下进行以控制患者术中疼痛,术中应用Swan-Ganz气囊漂浮导管监测肺动脉压,应用有创动脉压监测装置监测血压。分次的、有计划的无水乙醇硬化栓塞目标不是消除病变的供养动脉而是部分甚至全部的瘤巢直至临床症状和体征改善直至完全消失。每一个栓塞治疗前都要进行选择性和超选择性血管造影以便了解病灶的血流动力学特点,除了考虑AVM的造影特点,还要考虑治疗时瘤巢附近的正常小动脉或小静脉可能受到的影响、入路血管迂曲情况、之前外科手术对插管带来的影响等,才最终选择能到达瘤巢的入路血管实施硬化栓塞治疗。樱花治疗AVM的瘤巢可以使用同轴导管从动脉、静脉入路,也可以经皮穿刺直达瘤巢进行,对于Ⅰ、Ⅱ型AVM若仅考虑瘤巢以上三种入路均可到达病灶进行治疗。对于IIIa型因病变血管太细无法经皮穿刺,只能经动脉途径治疗,IIIb型经动脉途径和经皮穿刺途径均可。对于III型AVM禁忌从静脉入路进行硬化栓塞,因为这样既不能让栓塞材料到达瘘口,还会导致栓塞材料阻塞静脉流出道。因为这样会导致分流道压力升高,同时供养动脉违背破坏掉会导致畸形血管团的进展。从这个分类方法的定义也可以知道,II型AVM有多个迂曲的供养小动脉同时还有一个大的扩张的静脉成分,因此对于该型AVM的治疗更重要的是从静脉入路或经皮穿刺直接到达瘤巢,而不是从供养动脉硬化栓塞。经皮穿刺或经静脉入路可以避免动脉非超选择栓塞带来的邻近正常结构的异位栓塞。对于混合类型的AVM,经动脉和经皮穿刺途径联合应用首选,可以同时治疗AVM的两种成分。To determine the volume of ethanol used during embolizations and the rate of injection, test injections of the contrast medium were performed under fluoroscopic monitoring. The amount of ethanol used was based on the amount of contrast medium required to fill the AVM nidus without opacifying normal vessels. When maximum amounts of ethanol were used, the total dose did not exceed 1 mL/kg of body weight. In some cases, to achieve vascular stasis, a proximal inflow occlusion was performed during the ethanol injection using either an intravascular occlusion balloon catheter for the trunk and pelvis area or external pneumatic blood pressure cuffs for extremities. Of the embolic materials, absolute ethanol (99%) was used in most cases and 50-70% ethanol with a nonionic contrast medium (Xenetix 300; Guerbet, Cedex, France) was used in some AVMs of the hands or feet. Additional coil embolizations (Nester coil; Cook, Bloomington, IN) of the dominant outflow vein were performed in Type II AVMs by direct puncture or transvenous catheterization to reduce the amount of ethanol and to stabilize the thrombosis in the dominant outflow vein as Yee and Yakes previously reported (Fig. 2). After waiting 5 to 10 minutes after the ethanol injection, an arteriogram was performed to determine whether AVMs had been embolized completely. Complete embolization of at least one compartment of the AVMs required the meticulous repetition of the technique described earlier. When an elevated pulmonary artery pressure (more than 25 mm Hg) was sustained at the end of the session or a large amount of absolute ethanol was injected, the patient was kept at the intensive care unit for close pulmonary artery pressure monitoring and continuous administration of nitroglycerine (0.3-3.0 g/kg/min). All patients were closely followed up to identify any immediate or delayed complications.为了预判无水乙醇硬化栓塞时的注射速率,可以使用造影剂在透视下进行实验性注射,无水乙醇的用量随造影剂的用量而定,以不栓塞正常血管为宜,无水乙醇最大用量不超过体重(kg)mL,在某些情况下为了达到血管内栓塞剂滞留可以在躯干和盆腔血管内使用球囊阻断,也可以在肢体外使用血压计充气袖带加压法阻断静脉回流。栓塞材料选择上,99%无水乙醇使用最为广泛,但栓塞手、足AVM时50-70%酒精和非离子碘造影剂配比后应用较多。如Yee和Yakes之前所报道的一样,对于II型AVM经静脉或经皮穿刺病灶使用弹簧圈栓塞流出道可以减少无水乙醇用量,同时也可以使栓子形成更加稳固。无水乙醇栓塞5~10分钟后复查动脉造影了解病灶是否完全消失,完全治愈AVM需要将前述技术精细地反复执行。当治疗临近尾声肺动脉压超过25mmHg或大剂量无水乙醇注射后,患者需要在重症监护室监测肺动脉压并持续以0.3-3.0 g/kg/min泵入硝酸甘油,所有患者都需密切随访以防术后即刻并发症或延迟出现的并发症。As a rule, additional embolization was recommended if the symptoms and signs remained or the AVMs remained at follow-up imaging studies. The recommended time interval between embolotherapy is more than 2 months.作为一个原则,当症状没有改善或影像随访证实病灶未消失,建议再次硬化栓塞,两次治疗的间隔建议超过2个月。A diagrammatic presentation of approaches to ethanol embolotherapy according to the angiographic type.根据血管造影分类方法的硬化栓塞术入路示意图:图2.(A) The main target of type II AVMs is the venous component of the nidus. Therefore, the mainstay therapeutic approaches are transvenous (TV) and direct puncture (DP). Before ethanol embolization, coil embolization of the venous component of the nidus through a transvenous or direct puncture approach is often required to reduce the amount of ethanol and to stabilize the thrombosis within the large venous component.II型AVM主要病灶是瘤巢的静脉成分,因此主要的治疗入路是经静脉途径和直接经皮穿刺,在无水乙醇硬化治疗之前,经静脉途径或经皮穿刺使用弹簧圈栓塞病灶的静脉成分以减少无水乙醇用量,也能够阻塞流出道进而使栓子形成更加稳固。(B) Type IIIa AVMs. Only the transarterial (TA) approach is available. Because the fistula is too fine, direct puncture of the AVMs is not possible.对于IIIa型AVM只能经过动脉进行治疗,因瘘口过于细小,直接穿刺无法实现。(C)Type IIIb AVMs. These AVMs can be treated properly via transarterial (TA) and direct puncture (DP) approaches. However, if there are no obstacles in terms of access and safe embolization, the transarterial approach is preferred because of familiarity with arterial angiographic findings, the ease of detecting a normal artery arising near an AVM, and the direct puncture hazard whereby ethanol can leak into adjacent soft tissues. The treatment of type III AVMs via a transvenous approach is contraindicated. The approaches used for mixed types are combinations of those used to treat the individual types, but an approach that simultaneously treats all types present is preferred.对于IIIb型AVM,既能够经动脉途径治疗也可以经皮穿刺治疗,如果入路和栓塞安全性都没有困难,动脉入路仍是首选,因为我们对动脉造影表现更为熟悉,很容易发现AVM旁边发出的正常血管。直接穿刺的危害是无水乙醇可以经由穿刺点渗漏到邻近软组织。治疗III型AVM禁止经由静脉途径拟行入路。对于混合类型的AVM应多种入路方法联合应用,如有一种入路方法能解决混合病变的所有病灶,这个入路方法当然要作为首选。Evaluation of Angiographic Studies and Clinical Data影像资料和临床数据评估If an AVM that had been confined to one anatomic lesion at the initial workup showed two or more different types by angiography, the AVM was considered to be a mixed type of the two or more different types present. The therapeutic outcomes were assessed according to symptoms and signs and degree of devascularization at angiography. Cure was defined as complete resolution of clinical symptoms and signs, with 100% devascularization of AVMs at angiography. Partial remission was defined as complete resolution or an improvement in clinical symptoms and signs, with 50-99% AVM devascularization at angiography. No remission was defined as an improvement or no change in clinical symptoms and signs, with<50% devascularization at angiography. Aggravation was defined as a worsening of clinical symptoms and signs, regardless of the degree of AVM devascularization at angiography. Cure and partial remission were considered to be effective (successful) therapeutic outcomes of ethanol embolization.如果一个实体病变的AVM造影发现包括两种不同的类型,就可诊断为包括两种及两种以上病变的混合类型。效果的评估通过症状、体征和造影时血管床的减少程度来判定。临床症状和体征完全消失、造影时病变血管完全消失为治愈,临床症状和体征改善甚至完全消失、血管造影50-99%病变血管消失为部分缓解,临床症状和体征无改善、血管造影病变血管减少小于50%为无缓解,症状或体征恶化,不管病变血管减少多少均为进展,其中治愈和部分缓解被认为是临床有效。Results结果Results of assessing the angiographic types of the 66 AVMs based on the classifications are given in Table 1. The most common form of AVMs was type IIIb (45%, 30/66 AVMs). There were no type I AVMs. Twenty-one (32%) AVMs were categorized into the mixed form. Fifty-one (77%) AVMs had a type IIIb component, 22 (33%) AVMs had a type II component, and 14 (21%) AVMs had a type IIIa component.表格1有基于新的分类系统的66例患者资料,最常见的类型是IIIb型AVM(45%, 30/66),没有I型AVM,21个病变(32%)被分类到混合型,51个病变(77%)包含IIIb型AVM,22个病变(33%)包含II型AVM,14个病变包含IIIa型AVM。Therapeutic Outcome治疗效果The therapeutic outcomes according to the types of AVMs are also summarized in Table 1. Ethanol embolization was effective in 49 (cure 21, partial remission 28) (74%) of 66 patients (Figs. 3 and 4). Of the 19 patients waiting for further treatment, 9 patients were in the partial remission group and 10 patients were in the no remission group.With statistics, the therapeutic outcome for type II AVMs was better than for any other types (P < 0.05). No statistical difference in the therapeutic outcomes was found between the other types of AVMs (P > 0.05).依据AVM分型总结的治疗效果如列表1,无水乙醇硬化栓塞治疗66例患者,49例有效(其中21例治愈,28例部分缓解)(74%)。19位需要再次治疗的患者,其中9属于部分缓解组,10例属于无缓解组。统计下来,II型AVM治疗效果最好(P<0.05),其他各类型之间治疗效果无统计学差异(P>0.05)。Complications并发症 Complications related to ethanol embolotherapy according to the angiographic types of 66 AVMs are detailed in Table 2. Thirty-two (48%) of 66 patients had complications and there was no procedure-related mortality. Fifty-three (21%) complications occurred in 255 staged embolotherapy procedures. Four patients had major and minor complications together during the procedures. There were 43 minor complications in 28 patients (43/255 sessions, 17%; 28/66 patients, 42%). There were 10 major complications in 8 patients (10/255 sessions, 4%; 8/66 patients, 12%).无水乙醇硬化栓塞治疗66位AVM患者的并发症根据血管造影类型详细列举于表2,32位患者出现并发症,无操作相关的死亡病例。255个分阶段栓塞治疗,53个出现并发症。4例患者同时出现轻微并发症和严重并发症,28位患者发生43个轻微并发症(43/255次治疗,17%;28/66例患者,42%),8例患者出现10个主要并发症(10/255次治疗,4%;8/66例患者,12%)。图3.Figure 3 A 21-year-old male with type II AVM in the left calf. (A-C) Pretreatment posteroanterior angiography (arterial, late arterial, venous phase) shows plexiform arteriolar component (arrows) and a large venous component (arrowheads). (D) On superselective angiography, the components of a type II AVM can be easily identified.图3,21岁男性患者,左侧小腿II型AVM,A-C图分别为早动脉期-晚动脉期-静脉期显示网丛状的动脉成分和一个大的静脉成分,D图显示超选择动脉造影明确II型AVM。图4.Figure 4 A 42-year-old male with type IIIb AVM in the left calf. (A and B) Posteroanterior angiography (arterial and venous phase) shows multiple arteriolar and venulous components of the nidus. (C and D) Posteroanterior angiography (arterial and venous phase) after six embolotherapy sessions by the transarterial and direct puncture approaches shows a obliteration of 50% of the AVM.图4. 42岁男性左小腿IIIb型AVM,正位造影(A图为动脉期,B图为静脉期)显示包含多个动脉成分和静脉成分的病灶,C和D图显示经过6次经动脉和经皮穿刺治疗病灶一半已经消失。表2.躯干和肢体66个AVM无水乙醇硬化栓塞治疗并发症发生情况造影特点病人数治疗次数并发症数人并发症数主要并发症轻微并发症II型133348异位栓塞(2)脑梗死(1)膀胱梗死(1)皮肤坏死(4)IIIa型2312皮肤坏死(2)IIIb型30851624异位栓塞(1)感染(1)皮肤坏死(13)水泡(8)一过性神经损伤(1)II,IIIb型94237永久神经损害(2)感染(1)皮肤坏死(3)一过性神经损伤(1)IIIa,IIIb1292812急性肾功能衰竭(1)皮肤坏死(9)水泡(2)总计662553253
乙型肝炎母婴阻断技术我国为乙型肝炎病毒感染高发区,HBV母婴传播是病毒慢性携带的主要原因之一。自从采取新生儿注射乙肝疫苗和高效价乙肝免疫球蛋白联合免疫以来,婴儿感染率已明显下降,但仍然有10%婴儿阻断失败。研究表明:联合免疫失败的主要原因是宫内感染,而发生宫内感染的婴儿目前尚无补救措施。阻断母婴传播是乙肝的源头预防母婴传播的概念:指乙肝表面抗原阳性的母亲,尤其是表面抗原、e抗原双阳性的母亲,在妊娠、分娩、产后母婴密切接触及母乳喂养的过程中,将乙肝病毒传播给胎儿或者新生儿,引起婴儿HBV感染的过程。母婴传播的高危因素:1、孕妇体内乙肝病毒含量与母婴传播成正相关高风险:HBV-DNA>1x106 copeis/ml低风险:HBV-DNA 1X103-4 copeis/ml极低风险:HBV-DNA<1x103copeis/ml2、胎盘屏障的完整性3、胎儿的遗传易感性4、e抗原的相关性·母婴乙肝阻断技术研究进展:主被动免疫和抗病毒药物的应用:.血源性乙肝疫苗.基因疫苗.酵母重组疫苗·高效价乙肝免疫球蛋白的应用新生儿联合免疫孕期阻断+新生儿联合免疫·核苷类抗病毒药物的应用孕期抗病毒治疗+新生儿联合免疫分娩方式的探讨:有研究认为,HBV阳性母血渗漏入胎儿血循环的机率与产程长短关系密切;而剖宫产的胎儿不经过产道,可避免或者减少胎儿与母亲的体液接触,从而减少感染机会。术前,产妇尚未进入产程,因此宫缩强度较弱,时间较短,或者没有宫缩,减少了由于胎盘血管破裂而引起母血进入胎儿血循环的机会。但是,王建设等,采用联合免疫阻断母婴传播的观察到,HBsAg阳性率和慢性HBV感染率在不同分娩方式间无统计学差异,认为阴道分娩虽能增加产时感染的机会,但由于目前采用生后联合免疫,对产时感染可以采取较好的阻断效果,故并不主张采取剖宫产分娩的方式减低乙肝母婴的传播。降低产时传播的措施:1.避免和降低胎儿宫内窘迫的发生2.减少阴道操作,尽量避免困难的阴道助产,预防胎儿头皮损伤。3.胎儿娩出后更换无菌手套或有另一人实施新生儿处理。4.吸粘液时动作轻柔,避免过度吸引造成黏膜损伤。5.断脐前用干净的纱布清除断脐部位的粘液和羊水。6.断脐带后用无菌纱布覆盖脐带断端。7.注射前彻底清洁局部皮肤的血液和羊水,无菌纱布覆盖注射针孔。生后阻断措施:1.对HBsAg阳性母亲的新生儿,在出生后24h内尽早注射乙肝免疫球蛋白(HBIG),最好在出生12h内,剂量应≥100IU,同时在不同部位接种10ug重组酵母乙肝疫苗,可显著提高阻断母婴传播的效果。2.免疫接种后,应检测抗-HBs水平,如果抗HBs滴度<10mIU/ml,应加强免疫。有关母乳喂养:目前对HBsAg(+)或者HBsAg及HBeAg双阳性者是否母乳喂养,尚有不同意见。多项研究表明HBsAg(+)或者HBsAg及HBeAg双阳性者分娩的婴儿,生后采用乙肝免疫球蛋白和乙肝疫苗联合免疫后,母乳喂养不增加HBV的母婴传播。但有学者主张,母亲血双阳性且HBV-DNA阳性时,不宜采用母乳喂养。北京佑安医院对207例乙肝病毒携带产妇乳汁病毒携带情况的研究表明,14例乳汁HBV-DNA阳性者中,产妇HBV-DNA≥1X106,故产妇血液HBV-DNA<1x106者采用母乳喂养相对安全,但应注意在母乳喂养过程中,如果发生乳头皲裂或者新生儿口腔溃疡、腹泻等情况应暂停母乳喂养。乙肝病毒的宫内传播:HBV宫内传播的机制:1.胎盘途径2.PBMCs(外周血单核细胞)途径:PBMCs提供的HBV-DNA可能是HBV母婴传播的一个重要途径(母胎细胞转运)3.生殖细胞转运:此途径并不是宫内感染的主要途径。胎盘途径传播方式:1.妊娠晚期胎盘滋养叶细胞膜上产生P-C受体,其可与乙型肝炎病毒成分结合,以胞饮的形式进入胎盘细胞,但是胎盘细胞不含溶酶体,故不能将病毒成分杀灭,而是按浓度梯度以胞出的形式进入下一层胎盘组织内。2.乙型肝炎病毒成分在胎盘各层组织的分布,由母体面至胎儿面呈浓度递减趋势。3.合体细胞滋养层>细胞滋养层>绒毛基底层>毛细血管基底层>毛细血管上皮细胞宫内感染临床诊断指标:1.新生儿生于HBV携带母亲。2.出生日,接种乙肝疫苗和HBIG前,采集外周血检测到HBV复制标志物(非脐血)。3.持续存在3个月以上(以排除产道感染及一过性感染)。(第二届阻断HBV母婴传播和临床应用学术会)宫内传播的影响因素:1.母血中HBV-DNA含量2.HBV基因型3.遗传因素4.其他因素宫内感染发生的时间:宫内感染发生率为2-15%,主要发生在妊娠第三期。妊娠第一期:0-12w妊娠第二期:13-28w妊娠第三期:29-40w孕期HBIG应用:1.孕晚期28w32w 36w 分别给孕妇肌注HBIG 200-400u2.HBIG系高效免疫球蛋白的制剂,属于被动免疫,其中的抗HBs抗体可与HBsAg同时结合激活补体系统,增强体液免疫,消除HBV,降低母血中的病毒含量,可防止和减少正常细胞的感染,也可能减少HBV在母体的复制.3.孕期多次注射HBIG,抗HBs经胎盘输给胎儿,使其在宫内及获得被动免疫保护,预防了HBV的宫内感染。HBIG的对乙肝孕妇宫内感染的控制和预防具有十分重要的意义。4.但是近年循证医学资料的研究已经证明,肌注HBIG不能降低孕妇血液中病毒的含量,也不能降低母婴传播的风险,目前国内大多数学者已不主张应用。孕期核苷类抗病毒药物的应用:抗病毒治疗可有效抑制HBV复制抗病毒药物安全性分类:1.拉米夫定、替比夫定、恩曲他滨、替诺福韦被归入B类。如果应用这些药物给母亲和胎儿带来的收益超过风险,则可以应用。2.恩替卡韦、阿德福韦在动物实验中证实有胚胎和胎儿毒性,归入C类。3.普通干扰素和聚乙二醇干扰素由于具有抗增殖作用在妊娠期间应禁忌应用。WHO推荐的HIV母婴阻断方案:2009年11月30日WHO发布了HIV感染的妊娠期妇女抗病毒和HBV母婴阻断建议,其中拉米夫定是妊娠期推荐药物之一。拉米夫定:目前已有多项研究表明,妊娠期应用拉米夫定是安全的;能有效预防胎儿宫内HBV感染,减少乙肝疫苗免疫的失败率,提高母婴传播阻断率。替比夫定:1.属于妊娠期安全程度的B类药物,其优势在于, 抗病毒作用比拉米夫定快而强;第一年的抗病耐药率低。2.在妊娠期有可能更快地达到病毒复制的目的,降低病毒载量,减少母婴传播阻断的失败率。(资料来自首届助产会议上)
患者:病情描述(发病时间、主要症状、就诊医院等):母亲,67岁,半月前右腹部隐隐发痛,全身发黄,做加强cT后,胆管肿瘤堵塞胆管,肝脏长也有肿瘤,在安阳市人民医院。做介入手术打通胆道,胆红素由原来的280降到100多,体外排黄,胆管上的和肝脏上的肿瘤没动。想问:下一步出院后吃什么中药来控制肿瘤郑州大学一附院介入治疗科李明省:从你提供的资料来看,当地医院的治疗效果还是很不错的,总胆红素已经明显下降。接下来要做的事情包括:1.每天记录胆汁引流量,观察性状,保持水、电解质平衡。2.定期复查血常规及血生化指标了解胆红素,转氨酶、白蛋白及血象变化情况。3.若术中有胆道活检病理,可结合辅助放疗或化疗。至于口服中药来控制肿瘤,目前尚无循证医学数据支持,但是可以在增加营养摄入的同时口服些促进胆汁排泌的中药协助退黄。
替比夫定就像个淘气的孩子,只要医生看紧一点儿,它就不会出问题,但是,如果遇到不明内里的医生或者依从性不好的患者,可能就会有危险。 国际著名制药集团诺华,在中国患者因服用替比夫定引发横纹肌溶解症之后,修改了药品说明书。 2010年7月底,国家药监局(SFDA)一份通告,在数以百万计的乙肝患者中激起不安:他们服用的乙肝抗病毒药物—替比夫定(商品名:素比伏)和拉米夫定,可能引起罕见的不良反应—横纹肌溶解症,而这种疾病,严重的话会导致急性肾衰竭或多种脏器功能衰竭,进而危及患者的生命。相比拉米夫定,替比夫定的横纹肌溶解症发生率相对高一些,所以更为人所担心。 相比这份迟来的警示通告,是三起有迹可循的死亡病例:2008年12月,年仅18岁的安徽青年李力立,在服用替比夫定10个多月后,发生横纹肌溶解症而死亡,引发了一场长达1年多的官司;而在李力立之前,浙江省就已有两人,服用替比夫定后出现横纹肌溶解而死亡。 他们的生命已经无法挽回。而国家药监局这份通告,却让不少乙肝患者心生恐慌:替比夫定与横纹肌溶解症之间,有怎样的关联?这药还能安全使用吗? 北京地坛医院主任医师、《药物不良反应杂志》副主编蔡东,接到许多网民的咨询。在她看来,这并不意味着替比夫定和拉米夫定的安全性存在问题。 “替比夫定确实是有不良反应,它就像个淘气的孩子。但只要医生看紧一点儿,它就不会出这个问题了。”蔡东说,“我们参加研究的医生会督促病人,发现问题会及时处理。所以这个药在我手里头用,它就很安全,但不了解药物不良反应的医生或者遇到依从性不好的患者,它就变得不安全了。” 乙肝药物导致肌肉溶解? 2006年12月,当时只有16岁的李力立检查出乙肝,开始在安徽医科大学第一附属医院接受治疗。2008年1月31日,李力立根据医生的建议,服用替比夫定,一天一片,治疗时间是一年。 替比夫定商品名为“素比伏”,是诺华公司2007年2月在中国新上市的抗乙肝病毒药物。中国是乙肝大国,约有两三千万慢性乙肝患者需要治疗,而实际上估计至少有500万人在服用核苷类抗病毒药物。其中,拉米夫定在中国应用已有十余年,服用人数估计在200万以上。替比夫定的抗病毒作用强于拉米夫定,到2009年年底全球已有近10万患者服用,其中相当一部分是中国患者。 然而一年不到,2008年11月,李力立开始出现肌肉疼痛、无力等症状,当年12月8日遵医嘱停药,但病情持续加重。同年12月25日,李立力父母不得不将儿子转至上海瑞金医院治疗,但为时已晚。4天后,李立力离世。上海瑞金医院给出的死因是:横纹肌溶解综合症导致的多脏器功能衰竭。 位于上海的司法鉴定科学技术研究所司法鉴定中心出具的鉴定意见书认为:“李力立系服用抗乙肝病毒药物替比夫定所致的肌损害基础上,改用抗乙肝病毒药物拉米夫定进一步加重其损害,终致广泛的横纹肌溶解引起多器官功能衰竭死亡,属严重药物不良反应病例。” 然而,在当时的“替比夫定说明书”上,并没有提示横纹肌溶解的风险。对此,诺华公司给《南都周刊》的回复中提到,根据中国有关法律法规以及国际惯例,药品说明书应当由药监部门予以批准后才能使用,在大型临床试验中没有观察到横纹肌溶解,所以是不允许放在说明书里面的。 李力立过世6天后,也就是2009年1月4日,诺华变更了药物说明书,增加了“非常罕见横纹肌溶解的报告”字样。 前述司法鉴定意见书同时认为,“安徽医科大学第一附属医院对李力立的医疗行为存在一定不足,即医疗过失,属次要责任。 李力立父母的两纸诉状,分别将儿子生前就诊的安徽医科大学第一附属医院和替比夫定的生产厂家诺华制药告上了法庭。 据《大河报》报道,安徽医科大学第一附属医院认为,替比夫定的说明书上并没有横纹肌溶解综合症的提示。李力立的死,北京诺华制药应负更大责任。最终安徽医科大学第一附属医院赔偿了李力立父母24万元,并与李家达成了和解。 李家与诺华则进行了一场官司拉锯战。记者获悉,他们在2009年12月14日递交给北京市昌平区人民法院的起诉书中认为,“诺华公司在药物说明书上未对药物可能引起横纹肌溶解作出警示,未对需定期监测肌酸激酶作出警示”。 而诺华公司在给媒体的回复中称,对安徽患者家属遭遇的极大痛苦表示深切同情,因为患者生前曾使用过多个抗病毒药物,其中包括替比夫定。对于这个死亡事件,诺华做了大量的医学调查和研究工作,得出的结论是患者的死亡原因非常复杂,而且患者死亡和服用替比夫定药物之间并没有直接的联系。 双方各执一词,这场牵涉到制药业巨头的官司引来诸多媒体的关注,也让更多的乙肝患者和一线临床医生了解到,服用替比夫定可能引起的横纹肌溶解症。正因于此,促使国家药监局于今年7月,通报了替比夫定和拉米夫定可能引起罕见严重不良反应—横纹肌溶解。 两例死亡病例 今年5月,李家与诺华制药达成赔偿和解协议。但是,李力立并不是此药第一例不良反应的受害者。 诺华公司给《南都周刊》的回复称,2008年10月,诺华公司收到了来自北京的全球首例确诊的横纹肌溶解病例报告,这位患者经过治疗后已经完全康复。随后,诺华公司提出了说明书更新的申请。2009年1月4日,新说明书加入了“罕见横纹肌溶解”的不良反应。 实际上,在诺华公司声称的2008年10月首例确诊的横纹肌溶解病例之前,浙江已经有两例服用替比夫定后发生横纹肌溶解死亡的病例。 不过,诺华公司并不认为自己与浙江两例死亡病例存在关系。2010年3月,时任北京诺华制药有限公司首席科学官孔赋诚博士接受《合肥晚报》采访时说,诺华公司知道浙江出现的两例死亡病例,并在第一时间上报给了国家药监局。但孔赋诚称死亡原因不是横纹肌溶解。 《南都周刊》记者在两篇正式发表于学术刊物上的文章中,却找到了不一样的说法。 在2010年5月《中国药物警戒》杂志上,浙江省金华市药品不良反应监测中心朱瑞银及其同事,在《替比夫定致横纹肌溶解死亡1例》文章中称:2008年7月24日,浙江金华一位19岁男性患者在入院4天后死于横纹肌溶解导致的多脏器功能衰竭,而患者在最近一年多的时间使用替比夫定,与发生横纹肌溶解的时间关联性最大。 同年7月27日,浙江宁波解放军第113医院也收治了一位服用替比夫定后被诊断为横纹肌溶解症的25岁男性患者,该病人在入院后第9天死亡。这例死亡病例被收录在2010年4月《药物不良反应杂志》上,由解放军第113医院肾脏内分泌科医生吕飞娟及其同事报告:患者曾因四肢无力跌倒,被诊断为低钾性周期性麻痹,治疗时发现乙肝病毒感染。入院前10个月开始给予替比夫定治疗,肝功能逐渐好转。此次入院前8天,先是改用拉夫米定,入院后停用拉夫米定,但患者终因呼吸困难、循环衰竭而死亡。 真相是否被刻意隐藏? 无论是国家药监局、浙江省药监局还是诺华公司,都没有将这两例死亡病例向公众公开。 蔡东告诉记者,她听说过2008年浙江省的2例死亡病例。“当时通报的范围比较小,只是浙江省,也没有和其他省市共享这个药物不良反应的信息,而且那会儿药厂还有点儿遮遮掩掩的,不太愿意公开信息。像我们这些专门研究不良反应的人会知道,但其他地方的临床医生知道的可能不多。” 据知情人士透露,2008年10月15日,国家药监局曾向各地药监局下发了《关于2例素比伏死亡病例保管有关事宜的通知》,但这并非公开发布的文件,其具体内容至今还不为人所知。 而浙江省药监局2008年10月21日的一份内部文件也显示,国家药监局药物不良反应中心,收到了诺华公司报告的在浙江省境内发生的2例素比伏死亡病例。 这份内部文件还显示,浙江省药监局药物不良反应监测中心进行了现场调查,作出了初步的关联性评价,认为这两例患者属于严重的药物不良反应案例,要求相关监测机构和医院,高度关注替比夫定临床使用的安全性问题,并建议对正在使用替比夫定的患者,定期进行肌酸激酶、血象PH等检查,若发生肌肉酸痛的症状立刻就诊。 但这份文件的流传范围,仅限于浙江省。据多家媒体报道,李力立家的代理律师程林2009年调查取证时,曾以律师函的形式向浙江省药监局和国家药监局调阅相关材料,但均无功而返。律师尚且无法从药监部门获取相关的信息,更何况公众和广大乙肝患者? 熟悉药物不良反应通报流程的蔡晧东表示,药监局发布药物不良反应通报通常非常慎重。是药三分毒,服药后患者死亡的情况也不少见,但死亡有好多种因素,可能与患者本身疾病有关,在没有确认与药物有关之前,不会贸然发通报。实际上,以前中国的国家药监局都是跟着国外跑,国外通报了哪个药物,中国也通报哪个,“这次没跟着国外跑,国外没通报,咱们先通报了”。 记者在国家药监局的网站上发现,国家药监局此前向公众发布过3次有关替比夫定和拉米夫定的不良反应信息。 2008年3月15日发布的《药物警戒快讯》中写明:“欧洲药品管理局发布信息,建议在诺华生产的替比夫定说明书中加入新的警告,慢性乙肝患者在使用替比夫定存在发生周围神经病变的风险。”同年5月5日,国家药监局又一次发布《药物警戒快讯》,这一次引用了加拿大卫生部网站的消息,称“替比夫定与干扰素同时使用可导致周围神经病变”。 出现药物不良反应后,一般由患者、医生上报到药厂或者相关药物不良反应机构。像诺华公司,有专职机构监测药物上市后不良事件,会在24小时以内把所有监测到的不良反应进行报告。而数据表明,在向药监部门报告药物不良事件方面,诺华确实做得不错,2004年1月1日至2010年4月30日,国家药品不良反应监测中心收到替比夫定相关严重病例报告97例,其中70%来源于生产企业也就是诺华的报告。 2008年下半年开始,虽然开始陆续收到国内患者有关替比夫定的不良反应报告,但记者没有在国家药监局网站上查到类似的警示,直至2010年7月22日发布第30期《药物不良反应通告》通报,替比夫定和拉米夫定可能引起罕见的不良反应横纹肌溶解。 对此,李力立一案的代理律师程林说,他正和李力立父母商量是否起诉药监局,“这件事情上责任最大的是国家药监局,没有将药物不良反应的信息及时向社会公布,也没有规定药物出现未知不良反应后应该采取什么措施,这涉及人的生死问题,但这方面他们却没有做到,这是一种不作为。” 尊重生命换来的经验 尽管有关替比夫定可能引起的药物不良反应疑云重重,但多位肝病专家认为,这并不意味着替比夫定和拉米夫定的安全性存在问题。国家药监局的新闻发言人颜江瑛也称,横纹肌溶解的不良反应在临床上还是非常罕见的,如能尽早发现进行治疗,预后还是很好的。只有处理不及时,才会发展到横纹肌溶解的地步。 蔡东告诉《南都周刊》记者,拉米夫定是一种既能治疗艾滋病,又能治疗乙肝的药物。国内外医学文献显示,拉米夫定在治疗乙肝过程中,只有3例发生肌病和横纹肌溶解症和3例肾损害的报道,长期使用是非常安全的。而替比夫定是一种治疗乙型肝炎很有效的药物,被美国FDA批准为妊娠期间安全程度的B类药物,治疗4年肌肉相关不良事件的发生率为4%,其中确诊为肌病者仅0.9%,而横纹肌溶解实属罕见。 蔡东曾参加替比夫定上市前的临床试验,她向本刊记者证实,在临床试验中并没有出现横纹肌溶解的病例。但医生们发现,服用替比夫定的比服用拉米夫定的病人更容易出现血清肌酸激酶(CK)的升高,而这种酶的升高可能与肌肉损伤有关。但上市后,由于在中国的广泛应用,尤其是联合用药的患者增加,与替比夫定有关的肌病发生会有所增加,甚至导致横纹肌溶解症发生。 但参与临床实验的医生毕竟是少数,多数临床医生了解药物不良反应的途径,还是制药企业和国家药监局的网站上公开发布的信息。SFDA给《南都周刊》的回复称,广大医务人员及公众如需了解药物不良反应的详细信息,可以登录国家药监局的网站查询。 国内最大的乙肝患者论坛“肝胆相照”上,多名曾服用或正服用替比夫定的乙肝患者称,并没有得到来自医生有关药物不良反应的提醒,大多是通过说明书和上网,了解到替比夫定的不良反应信息的。而在沈阳,出于替比夫定安全性不了解,一些患者做出殴打医生等过激行为。 “它抗病毒比拉米夫定要强,价格又不如恩地卡韦贵,所以上市后许多医生愿意用这个药,现在药监局一通报,又一下不敢用这个药”。在蔡晧东看来,在医生这个层面,对替比夫定的用药多少有一些混乱。而乙肝患者完全没有必要因为药监局的通报过于担心,更不要盲目停药,随便换药,这个药基本上还是安全的,给患者带来的好处也明显高于那些少见甚至罕见不良反应的风险。 在北京302医院,服用替比夫定或服用会引起CK升高药物的,一般建议患者两个月查一次CK值。这家医院的刘士敬医生说,大医院可以有这个条件,但小医院根本没有这个条件。而且,一些大医院即使有条件,也没有相应的要求或制度。 李力立就没有被主治医生告知服用替比夫定后应该定期随访监测,在他服药后长达10个多月的时间内,从未检查过CK值。而他就诊的安徽医科大学第一附属医院,是卫生部首批三级甲等医院之一,也是安徽省规模最大的综合性教学医院。 前述浙江的两例死亡病例出现后,医院和地方药品不良反应监测中心也发表论文进行了反思。其中,金华那位19岁患者相继使用拉米夫定、阿德福韦酯、替比夫定三种抗乙肝病毒药物,却未对CK升高等不良反应进行及时有效的监测,最终导致横纹肌溶解症发生。宁波那位25岁患者服用替比夫定前,“医院未进行CK复查,也未考虑到患者原有肌病,用药期间未进行CK监测和肌肉症状的随访,从而导致患者横纹肌溶解的发生”。 实际上,在替比夫定上市前的临床试验中,虽然没有关于横纹肌溶解的病例报告,但2007年已经有公开发表的英文论文指出,临床研究显示,替比夫定引起肌肉症状的发生率为2.35%。替比夫定上市前后,也有多位国内外专家提醒,使用替比夫定的患者要注意监测CK水平及肌肉症状,出现肌病时立即停用替比夫定,以及其他可能导致肌病或CK升高的药物。但遗憾的是,这样的警示信息在很多医院和医生那里没有得到充分的传播和重视。 蔡晧东说,“新药相关的严重的不良反应的经验是病人的生命和鲜血换来的,我们应该尊重病人的生命和鲜血,(无论是药监局还是制药企业)获知不良反应信息之后,要及时告诉一线的医生,避免以后的病人付出生命的代价。”
原发性肝癌是我国发病率较高的恶性肿瘤,黄疸是其常见的合并症状。一般说来,原发性肝癌所合并的黄疸大致可分为肝细胞性黄疸和阻塞性黄疸。两者无论从发病机理、临床表现直到处理、预后等都有所不同。原发性肝癌合并阻塞黄疸的主要原因可能有:①癌肿直接压迫(或侵犯)主要胆管引起黄疸;②肝癌癌栓阻塞胆管引起黄疸;③肝癌发生肝门淋巴结转移压迫胆管引起黄疸;④肝癌并发有非肿瘤性胆管梗阻,如胆管结石等。肝脏原发肿瘤侵犯胆管可能通过以下途径¨:①癌肿直接侵入薄壁的肝内胆管;②癌细胞侵入静脉及淋巴管,逆行侵入肝管壁;③癌细胞沿神经鞘的间隙侵入胆管壁;④门静脉癌栓侵犯邻近胆管;⑤肝内肿瘤转移至胆管壁上的营养血管,穿破胆管上皮,进入胆管腔内。肝癌合并胆道癌栓导致阻塞性黄疸的机制主要有以下3种 :①癌肿侵犯胆管壁并生长,在管腔内依胆管腔形状形成铸型癌栓,与原发肿瘤相连。②癌肿坏死碎片脱落,进入远处的胆总管内导致胆道梗阻。③来自癌肿的出血形成癌性血栓致胆道部分或完全梗阻。肝癌并发胆道癌栓多首先表现为阻塞性黄疸及胆道感染的症状,易与胆石症、胆道出血、肝炎及胆管癌等混淆。黄疸可以进行性加重,亦可间断眭加深或减退,部分病人可因胆道出血而有胆绞痛;既往多有乙肝病史,如AFP明显增高、影像学检查发现有肝脏肿块,应高度怀疑。B超、CT及 MRI对该症均有较高的正确诊断率,但如果诊断仍有疑问,ERCP、MRCP在肝癌并发梗阻性黄疸的诊断上具有重要价值。 影像学表现:影像学表现为胆管腔内的充盈缺损,成卵圆形、纺锤形、蚯蚓状、杯口状不规则形,有的因癌栓不完全阻塞胆道并有反复出血,可呈蜂窝状。梗阻部位的胆管成不规则狭窄或全部梗阻,其近端的胆管有不同程度的扩张。临床实践表明由胆道癌栓所致的阻塞性黄疸,行肝癌切除和胆道取栓后常可使黄疸减退,提高生活质量。延长生存期。虽然各国肝癌发病率差异很大,但各国肝癌病人并发胆道癌栓的发生率却非常接近,约在0.9% 一4.9% ~6 %。近年来肝癌合并胆道癌栓的报道逐渐增多,但对小肝癌并胆道癌栓的认识却不够。有作者认为小肝癌较少发生胆管癌栓,只有癌体增大、癌细胞突破包膜向外侵润生长时才可能发生。我们的临床研究发现,胆道侵犯的原因与肿瘤生物学特性及生长部位有关,而与肝癌的大小关系不大。此与彭宝岗报道一致。本组有2例在术中证实为胆管癌栓时,却未能找到肝内原发灶,只是在术后跟踪随访时,分别在术后1个月、5个月才发现肝脏肿块。因此,如术中经仔细探查仍未能找到原发病灶,术后一定要跟踪复查,定期行彩超、SCT、DSA 等检查,一旦发现原发病灶可行TACE+RAF治疗,仍能取得良好的疗效。临床处理: 1、对于肝功能较好、因肿瘤压迫(或侵犯)主要胆管而引起黄疸的患者,如能行手术治疗,则首选切除肿瘤,清除胆管癌栓。 2、因肝功能较差或因肿瘤所在的部位而不能行手术治疗的患者,在弄清胆管受压的具体位置之后,可通过ERCP行胆道内置管(塑料内置管)内引流或鼻胆管外引流,或行PTCD外引流,以解除黄疸,然后再接受TAE或PEIT治疗,个别患者在肝脏功能得到一定程度的改善、或肿瘤经TAE、PEIT治疗缩小后,还有可能获得手术治疗的机会。 所谓胆道内置管内引流是指在胆道的狭窄部位置放一根导管,其两端分别位于狭窄部位的上下,将胆汁引流入肠腔。鼻胆管是指引流管的一端置于胆管狭窄部位以上,另一端经鼻腔引出体外,为经ERCP的胆道外引流。因其须经咽喉部引出,会给患者带来较大不适,且每日还会造成胆汁的大量丢失,故不宜置放太久,医生在决定置管类型时应考虑到这一点。 当然,鼻胆管也有内置管所不可替代的优点,即易于控制管道的通畅情况,还可经其处理胆道的感染等。此外,在行PTCD引流时如能将引流管置放到胆管的狭窄段以下,则可起到解除黄疸、改善全身状况的双重作用,既减少甚至避免胆汁的大量丢失,又有利于营养物质的消化吸收。3、对于肝癌癌栓阻塞胆管的处理,仍然以手术清除为首选。肝癌根治性切除连同胆道癌栓取出术有一下优点:①切除肝癌原发病灶,防止癌栓继续侵入胆管;② 解除胆道高压,缓解症状;③使后继治疗如免疫生物治疗、介入治疗等得以顺利进行。胆管癌栓不同于门静脉癌栓,后者主要靠门静脉血供,不易清除干净,前者只要切除肝脏的原发灶,清除胆管内的继发灶,就能达到治疗目的。我们发现绝大多数癌栓与胆管壁无紧密粘连,癌栓易被取出。癌栓质松软,易坏死、出血、脱落、易清除,取栓时,胆道可能出血,只要原发灶切除后出血可停止。肝癌切除并胆道癌栓取出后,综合治疗也十分重要,术后早期经T 管定期滴注化疗药(首选5一FU、MMC)、TACI及免疫和生物学治疗可能提高疗效。此外,还可选择先行胆道置管内(或外)引流,解除黄疸,改善患者的身体状况及生存质量,然后根据具体情况予TAE或其他针对肿瘤的治疗措施。不宜手术治疗的胆管癌栓患者以置放金属内置管为宜,因塑料管管径较小,易被癌栓堵塞,且胆管内癌栓也不易完全消除。如金属管被癌栓堵塞,还可在金属管内再置入塑料管。 对于一些癌栓不多、胆道梗阻并不完全者,有时单行TAE治疗也可收到理想的效果,这是因为胆管内癌栓的血液供应与肝内肿瘤一样,仍然以肝动脉为主之故。个别情况下,肝癌仅仅以胆管癌栓的形式出现,应用现有的B超、CT、MRI等影像学检查手段均难找到肝脏内的原发肿瘤,此时诊断就较为困难。但不管肿瘤源于何处,外科手术或胆道置管引流以解除黄疸都是可行的(行ERCP时所取的活组织检查亦可起到诊断的作用)。 4、如为肝门肿大的转移淋巴结压迫胆管引起黄疸,胆道置管也很有必要。尽管针对已发生转移的肿瘤尚缺少有效的治疗手段,但充分引流胆管仍可不同程度地改善患者的生存质量,延长生存时间。 5、如果原发性肝癌患者原本就有较为严重的肝细胞性黄疸,以后又因肿瘤压迫或胆管癌栓引发了阻塞性黄疸,虽然其处理更为棘手,但积极的胆道引流有可能打断“梗阻性黄疸→细胞性黄疸”这一恶性途径,以达到部分甚至较大程度地改善肝脏功能、提高生存质量并为进一步治疗创造条件之目的。 6、如为原发性肝癌合并胆管结石,则应视具体情况进行处理。能手术治疗则可同时切除肿瘤,取出结石,解除胆道梗阻;不宜手术治疗者仍宜积极引流胆道,解除胆道梗阻(感染),然后针对肝脏肿瘤选择合适的治疗措施。 7、原发性肝癌阻塞性黄疸时治疗,因患者癌细胞的侵袭以及治疗过程中对患者机体的伤害,患者正气多虚弱,免疫力低下,易造成癌细胞的扩散和转移,辅以中医药治疗必不可少。
进入2l世纪,随着现代医学的发展和肿瘤分子机制研究的逐步深入,全球抗肿瘤药研发硕果累累。自2005年至今,美国食品与药品管理局(FDA)和欧洲药物管理局(EMEA)正式批准上市的抗肿瘤药有24个(孤儿药除外)。据不完全统计,2010年全球正处于临床研究阶段的抗肿瘤新药达470多个,共涉及2 760余项临床研究,其中Ⅲ期临床试验达231项,涉及新药50多个。本文拟就其相关研究进展作一综述,供医、药、护及药物研究人员参考。1 细胞毒药物 细胞毒药物是经典的抗肿瘤药,疗效肯定。虽然其毒副作用较大,但由于替代性药物缺乏,一直是化疗的基础药物。其主要有以下几类:1.1 烷化剂 曲贝替定(Trabectedin,强生制药公司)是首个海洋来源抗肿瘤药,为在海鞘中提取的四氢喹啉类生物碱的半合成品。除了可阻滞肿瘤细胞在G1/G2周期的分化外,还可抑制血管内皮细胞生长因子(VEGF)的分泌及VEGF受体(VEGFR)-1的表达。2004年,其在欧、美已被指定为治疗急性淋巴母细胞白血病、软组织肉瘤和卵巢癌的孤儿药。2007年,EMEA正式批准其用于进展型软组织肉瘤的二线治疗。 盐酸苯达莫司汀是携带1个嘌呤样苯并咪唑环的氮芥衍生物,兼具烷化剂和嘌呤类似物的双重作用机制。2003年,盐酸苄达莫司汀在德国上市,2008年在美国上市。用于慢性淋巴细胞性白血病(CLL)和惰性B细胞非霍奇金淋巴瘤(NHL)的治疗。1.2 抗代谢药 奈拉滨(Nelarabine,葛兰素史克公司)为脱氧鸟苷类似物9-β-阿糖鸟嘌呤(ara—G)的前体药,在体内活化为5-三磷酸ara-GTP,选择性地在T细胞中积累从而抑制脱氧核糖核酸(DNA)合成,导致癌细胞死亡。2005年,美国FDA批准其用于至少2种化疗方案治疗无效或治疗后复发的T细胞急性淋巴细胞性白血病或淋巴瘤。该药单用抗T细胞淋巴瘤效果较强,治疗复发或抵抗患者总有效率为41%,完全缓解率可达31%,无进展生存期(PFS)为20周,1年生存率为28%。 抗叶酸制剂Pralatrexate(Allos制药公司)由甲氨蝶呤改进而成,抑制二氢叶酸还原酶。2009年,美国FDA批准其单用于复发/难治性T细胞淋巴瘤治疗,给药时定期肌肉注射维生素B12, 每日口服叶酸可减轻与治疗相关的血液学毒性和黏膜炎。1.3 铂类抗肿瘤药 赛特铂(Satraplatin,百时美施贵宝公司)系具环己基氨结构的第3代铂络合物抗肿瘤药。口服给药吸收良好,疗效与顺铂、卡铂相近,与顺铂无交叉耐药性,不良反应为呕吐,未发现肾、肝及神经毒性。目前,正对前列腺癌、小细胞肺癌(SCLC)和非SCLC(NSCLC)、卵巢癌进行Ⅲ期临床试验。1.4 蒽环类抗肿瘤药 匹杉琼(Pixantrone,Cell Therapeutics公司)为米托蒽醌衍生物,其作用机制与米托蒽醌相似,可嵌入细胞DNA,抑制拓扑异构酶Ⅱ(TopoⅡ)。该药单用治疗NHL的完全缓解率约为20%,联合治疗时可达59%。目前,美国FDA正在审核其治疗复发性、侵袭性NHL的上市申请。EMEA已授予其弥漫性大B细胞淋巴瘤的孤儿药资格。另外,匹杉琼在体内、外均表现出免疫活性,故将来极有可能也作为免疫抑制剂应用。 氨柔比星(Amrubicin,住友制药)是第3代合成蒽环类拟似物,与多柔比星的作用机制略有不同,主要通过抑制TopoⅡ的活性,最终导致DNA的断裂而抑制肿瘤细胞增殖。已于2002年在日本获得批准上市,用于NSCLC及SCLC的治疗。2008年,美国FDA授予其SCLC的孤儿药资格。1.5 微管稳定剂 目前,临床应用的主要有紫杉烷类和长春碱类化合物,新开发的微管稳定剂分为4类:萜类(紫杉烷类)、大环内酯类(如埃坡霉素、伊沙匹隆)、多羟基四烯内酯类和甾类化合物。紫杉烷类代表产品紫杉醇自1992年由美国FDA正式批准上市以来,已在40多个国家获准上市,主要用于乳腺癌、卵巢癌和NSCLC的一线治疗。但紫杉醇的低溶解度、低有效利用率及P-糖蛋白相关耐药等问题限制了其临床应用。因此,紫杉烷类相关研究主要是紫杉醇新剂型研究及新化合物的开发2方面。纳米紫杉醇((Capxol,美国阿博利斯公司)是首个获准的非溶解纳米蛋白质结合颗粒类化疗药。该制剂以人血白蛋白作为共聚物包裹紫杉醇形成纳米悬浮液,利用白蛋白受体的内在途径传输药物透过肿瘤新生血管内皮细胞壁,使紫杉醇直达肿瘤间质。Ⅲ期临床试验显示,与紫杉醇相比,纳米紫杉醇疗效可增加1倍,并明显延长PFS与总生存率,耐受性良好。2005年,美国FDA批准该药用于治疗转移性乳腺癌。我国在2009年引进。2004年上市推广注射用紫杉醇脂质体(力扑素,南京思科药业)是我国食品药品监督管理局(SFDA)批准的第1个注射用脂质体药,也是国际首次上市的注射用紫杉醇脂质体药。聚谷氨酸紫杉醇是一个可生物降解的大分子聚合物,水溶性高分子多聚谷氨酸与紫杉醇结合后溶解度增加8万倍,且由于聚合体体积增大,不易透过正常组织血管,但对肿瘤组织具有被动靶向作用。Ⅲ期临床研究表明,与吉西他滨和长春瑞滨相比,该药对于NSCLC不仅疗效更好,且不良反应更轻。 埃坡霉素(Epothilones)是一类十六元环的大环内酯类药,作用机制与紫杉醇相似,但对紫杉烷类耐药的动物模型仍具较强活性。伊沙匹隆(1xabepilone,百时美施贵宝公司)促进微管聚合能力是紫杉醇的2倍,在极低浓度下即具有杀灭肿瘤细胞的作用,对紫杉醇不敏感或耐药的患者也表现出较好疗效。Ⅲ期临床试验结果表明,对于蒽环类和紫杉烷类治疗耐药或转移的乳腺癌患者,伊沙匹隆能提高卡培他滨的疗效。2007年10月,经美国FDA批准用于多药治疗无效的转移性或进展性晚期乳腺癌,成为第1个上市的半合成埃坡霉素B类似物。目前,该公司正积极筹备在中国上市申请。 Eribulin(卫材公司)为软海绵素B的大环酮类衍生物,属微管动力抑制剂,其甲磺酸盐在蒽环类抗生素和紫杉烷类化疗无效的顽固性、晚期乳腺癌患者身上显示了良好的效果,与其它药物联用时亦能产生协同作用。2 内分泌治疗药 进入21世纪,有多个肿瘤内分泌治疗药陆续上市,除了已进入我国市场的醋酸亮丙瑞林(2000年)、曲普瑞林(2001年)外,已在国外上市或即将上市的还有氟维司群(Fulvestrant,阿斯利康公司)、阿巴瑞克(Abarelix,Praecis制药公司)、Degarelix、组氨瑞林(Vantas,维勒拉制药公司)等。 氟维司群是一种新型雌激素受体拮抗药,能结合、阻滞和降解乳腺癌细胞的雌激素受体,对雌激素受体无激动作用。2002年4月和10月分别在美国和欧盟上市,用于抗雌激素药治疗无效的绝经后激素受体阳性转移性乳腺癌。是第1个可用于晚期他莫昔芬顽固性乳腺癌治疗的抗雌激素药,每月肌肉注射给药1次,具有较好的依从性。 注射用阿巴瑞克混悬液为促性腺激素释放激素拮抗药,2003年美国FDA批准其用于不适用黄体生成素释放激素(LHRH)激动药疗法以及拒绝接受手术治疗的晚期前列腺癌患者的姑息疗法,其作用特点是去势作用强而快。与亮丙瑞林相比,虽然在降低血清前列腺特异抗原(PSA)和维持睾酮去势水平方面是等效的,但阿巴瑞克的作用更快、更有效。 Degarelix(商品名:Firmagon,Ferring制药公司)也是促性腺激素释放激素拮抗药,通过抑制睾酮来延缓前列腺癌的生长和恶化。它避免了传统治疗初期睾酮浓度激增促进肿瘤生长的现象,降低睾酮浓度的效果可与亮丙瑞林相媲美,且速度更快。应用2周、1个月、3个月后PSA分别降低64%、85%、95%,在治疗的整年中始终抑制PSA。 组氨瑞林通过长期抑制垂体促性腺激素的释放阻滞卵巢和睾丸功能,为Hydron(吸水性丙烯酸聚合物)植入剂,只需每年给药1次。2004年10月,经美国FDA批准上市用于前列腺癌的姑息疗法。3 免疫治疗药 近年来,随着免疫学理论不断丰富,免疫学技术不断推陈出新,肿瘤抗原尤其是T细胞识别的肿瘤抗原不断被发现,以抗体疗法、T细胞疗法和肿瘤疫苗为代表的肿瘤免疫治疗已取得显著进展。免疫细胞CD4是T细胞的标志,在多数T细胞淋巴瘤中表达。Zanolimumab(HuMax-CD4,Humax公司)是人源化抗CD4单克隆抗体。一项正在进行的Ⅱ期临床试验中期分析提示,该药治疗21例难治复发的CD4阳性的外周T细胞淋巴瘤(PTCL),缓解率为23.8%。该药的T细胞淋巴瘤Ⅲ期研究正在开展中。 CD20是B细胞表面的一种Ⅲ型钙离子通道跨膜蛋白,过度表达于B细胞淋巴瘤、毛细胞白血病以及慢性B淋巴细胞白血病。全球首个单抗制剂利妥昔单抗(美罗华)和首个放射免疫复合物替伊莫单抗(泽娃灵)的靶点均为CD20,最新上市的药物是Ofatumumab(商品名:Arzerra,葛兰素史克公司,2009年),用于对氟达拉滨和阿伦单抗耐药的慢性淋巴细胞白血病的治疗。Ofatumumab是一个全人源的抗CD20抗体,与美罗华相比,抗体依赖性细胞介导细胞毒作用效应近似,诱导细胞凋亡效应弱。用于氟达拉滨和阿伦单抗耐药的慢性淋巴细胞白血病和氟达拉滨耐药并伴显著淋巴结腺体肿大的慢性淋巴细胞白血病的治疗,有效率分别为58%和47%,中位PFS及总生存期分别为5.7、13.7个月和5.9、15.4个月。 NGR-hTNF(NGR008,MolMed公司)是一种肿瘤导向肽(NGR)和人源性肿瘤坏死因子(TNF)的血管靶向融合物,可以选择性地与氨肽酶N结合。虽然该药的Ⅱ期临床试验仍在进行中,但已分别被美国FDA和EMEA授予肝细胞癌的孤儿药身份。 细胞毒性T淋巴细胞相关抗原-4(CTLA4)是共刺激分子B7的受体,主要表达于被激活T细胞表面,与B7结合后能抑制T细胞的激活。作为CTLA4阻滞药的单克隆抗体,可特异地解除CTLA4对机体免疫抑制,激活T细胞,产生抗肿瘤作用。目前,已有百时美施贵宝公司和辉瑞公司的Ipilimumab和Ticilimumab进入Ⅲ期临床试验;Tremelimumab用于治疗耐药/复发的黑色素瘤也取得了较好的疗效。 由德国Trion和Fresenius公司共同开发的Cammaxomab是由单抗HO-3衍生的一种三功能抗体,能同时激活T细胞和辅助免疫细胞,从而破坏拥有表面抗原上皮细胞黏附分子(Ep-CAM)的靶肿瘤细胞。2009年4月,在欧洲获准用于由Ep-CAM阳性上皮源性转移瘤所引起的恶性腹水治疗。 肿瘤疫苗是直接应用肿瘤抗原进行主动免疫治疗的一种方法,早期批准上市的癌症疫苗主要有膀胱癌疫苗、结肠癌疫苗和黑色素癌疫苗。近期上市的疫苗有Gardasil(默克公司,2006年)和Cervarix(葛兰素史克公司,2007年),均为宫颈癌疫苗。Gardasil能预防人乳头瘤状病毒(HPV)6、11、16、18型感染长达5年,降低宫颈癌的发病率;Cervarix能有效预防HPV l6/18型感染4.5年。4 基因治疗药 载突变细胞周期控制基因纳米粒注射剂(商品名:Rexing,伊佩尤斯生物技术公司)是全球首个获准上市的载基因纳米粒药(2003年美国FDA批准其为治疗胰腺癌的罕用药物),由包裹外层、基质、壳体、多种酶和基因物质等成分组成的纳米粒,可释放致命的杀伤部件,选择性地杀死癌细胞并阻滞其相关的血液供应而不损伤正常细胞和健康组织,因而可减少肿瘤对人体的危害,延长存活期并改善患者的生活质量。对包括靶向生物制剂在内的其它药品治疗失败的病例具有极高的疗效。米伐木肽注射剂(Ark公司)是一种腺病毒载体定位码基因注射剂,法国医药管理局于2009年批准其作为罕用药物与更昔洛韦合用,用于术后恶性神经胶质瘤的辅助治疗。二者相互作用摧毁处于分裂的细胞,对健康脑细胞无害。 G3139(Oblimersen,Genta公司)是针对Bcl-2的反义寡脱氧核苷酸(ASODN)药。据Badros等的Ⅱ期研究报道,G3139、地塞米松和沙利度胺联合治疗复发的多发性骨髓瘤分别有6.25%、38.7%和19.4%的患者达到完全缓解、部分缓解及显效,PFS和中位生存期分别为12、17.4个月。 OGX-011(Oncogenex公司)是一种靶向抗细胞凋亡因子聚集素翻译初始位点的21bp的ASODN,可抑制聚集素表达水平,加速凋亡,延迟复发。该药于2009年10月获得美国FDA审核资格,合并多西他赛治疗乳腺癌,有效率达33%,中位无疾病进展期8个月,不良反应与多西他赛单用相似。5 靶向抗肿瘤药5.1 酪氨酸激酶抑制剂 蛋白酪氨酸激酶(PTK)是多种肿瘤最常见的生长因子受体,抑制其活性可破坏肿瘤细胞的信号传导,抑制肿瘤细胞增殖和新生血管形成,而对正常细胞影响较小。常见的受体型包括表皮生长因子受体(EGFR)家族、胰岛素受体(IGFR)家族、血小板衍化生长因子受体(PDGFR)家族、VEGFR家族、纤维细胞生长因子受体(。FGFR)家族等。非受体型包括SRC、ABL、JAK、ACK、CSK、FAK、FES、FRK、TEC、SYK家族等。以PTK为靶点的单克隆抗体、小分子酪氨酸激酶抑制剂(TKI)是近年抗肿瘤药研究的热点。2005年之前,美国FDA批准以PTK为靶点的单克隆抗体曲妥珠单抗(1998年)、贝伐单抗(2004年)和西妥昔珠单抗(2004年)和小分子酪氨酸激酶抑制剂伊马替尼(2001年)、吉非替尼(2003年)、埃罗替尼(2004年)等靶向药物应用于临床。2005年后TKI制剂不断上市,且多靶点药已成为新的研究方向。 尼妥珠单抗(Nimotuzumab)是我国首个以EGFR为靶点的人源化IgGl单克隆抗体药,2005年SFDA批准其与放疗联合用于治疗EGFR阳性表达的Ⅲ/Ⅳ期鼻咽癌。 帕尼单抗(Panitumumab)是2006年9月上市的全球第1个完全人源化IgG2κ单克隆抗体,靶向作用于EGFR,用于治疗化疗后病情仍然进展或转移的结直肠癌。与西妥昔单抗等IgGl亚型单克隆抗体相比,IgG2亚型的帕尼单抗抗体依赖性细胞介导细胞毒作用较弱,t1/2更长,免疫耐受性更好。 达沙替尼(Dasatinib,百时美施贵宝公司)临床用于对既往治疗失败或不耐受的慢性粒细胞白血病(CML)患者,同时还用于治疗对其他疗法耐药或不耐受的费城染色体阳性的成人急性淋巴细胞白血病(ALL)患者,2006年6月美国FDA批准上市。达沙替尼治疗伊马替尼耐药急性骨髓性白血病(AML)的血液学缓解率和完全缓解率分别为64%、45%,严重不良反应主要为中性粒细胞减少、血小板减少以及腹泻。 拉帕替尼(Lapatinib,葛兰素史克公司)是一种可逆性ErbBl、ErbB2酪氨酸激酶抑制剂,2007年3月在美国首次上市,用于治疗晚期乳腺癌。 尼洛替尼(Nilotinib,诺华制药)是第2代选择胜更强、疗效更显著的Bcr-Abl酪氨酸激酶抑制剂,2007年10月美国FDA批准用于伊马替尼耐药的CML的二线治疗。在临床试验中,42%的对伊马替尼耐药的慢性期Ph+CML患者出现了明显的细胞遗传学缓解,异常染色体减少或者消失;而在处于加速期的患者中,也有31%的患者能够获得同样的效果。该药治疗胃肠道间质瘤(GIST)的临床研究也进入Ⅲ期阶段。 Pazopanib(葛兰素史克公司)是同时作用于VEGFR-1、VEGFR-2、VEGFR-3、PDGFR、c-kit等多个靶点的TKI,2009年获得美国FDA批准用于治疗晚期肾癌。对于化疗耐受的晚期肾癌患者,客观有效率30%,在PFS和风险方面都得到了大大的改善。 PLX-4032(罗氏公司/Plexxikon公司)是目前最有希望的非受体型酪氨酸激酶抑制剂,选择性抑制位于MAPK/ERK途径入口处的BRAF蛋白。目前,正处于恶性黑色素瘤的Ⅲ期临床试验,是首个进入临床试验的V600E突变的BRAF酪氨酸激酶抑制剂。I期临床试验显示,该药对V600E突变的黑色素瘤患者,有效率达42.9%,而对未突变者基本无效。 IMC-11F8(ImClone公司)是抑制EGFR的完全人源化IgGl单克隆抗体,目前正在开展该药联合培美曲塞与顺铂或者吉西他滨与顺铂一线治疗NSCLC的2个Ⅲ期临床研究,预计2012年完成试验。 BIBW 2992(勃林格殷格翰公司)与帕尼单抗和Neratinib(惠氏制药研发的一种口服不可逆HER-2和EGFR激酶抑制剂,处于I/Ⅱ期临床试验)相似,是新一代的不可逆的ErbBl和ErbB2双通道抑制剂,该药对吉非替尼和埃罗替尼耐药的患者仍有效,已进入用于治疗NSCLC的FDA快速审批通道。该药针对乳腺、前列腺、头颈部及神经胶质瘤等部位肿瘤的Ⅱ期临床研究也在进行中。 伯舒替尼(Bosutinib,惠氏公司)是强效Src和Abl激酶双重抑制剂,既能抑制多种人肿瘤细胞中Src蛋白的自主磷酸化,也能抑制Src和Ab底物的磷酸化过程,具有高效的抗增殖活性,可抑制CMI。细胞的增殖和存活,对伊马替尼、达沙替尼和尼罗替尼等已产生耐药的CML,或ALL患者也取得了较好的疗效。目前,正在进行CML的Ⅲ期临床研究。 Motesanib(安进公司)能选择性地作用于VEGFR-1、VEGFR-2、VEGFR-3、PDGFR和c-kit受体,可致内皮细胞程序性死亡增加和血管面积减少,抑制肿瘤血管生成并诱导肿瘤消退。目前,本品NSCLC的Ⅲ期临床研究正在进行中;其GIST、甲状腺癌、乳腺癌、卵巢癌等适应证的研究也处于Ⅱ期临床研究阶段。 凡德他尼(Vandetanib,阿斯利康公司)是口服小分子EGFR、VEGFR、RET多靶点酪氨酸激酶抑制剂。Ⅱ期临床显示,单用或与多西他赛联合用药,其在NSCLC患者的二线/三线治疗中均有效。 Vatalanib(拜耳/诺华)是经高通量筛选出的VEGF、PDGF、c-kit多靶点小分子TKl,对VEGFR-2作用最强。与FOLFOX方案联合治疗转移性结直肠癌的2个Ⅲ期研究正在进行中。目前,发现体内乳酸脱氢酶水平较高的患者疾病PFS显著提高。 BIBtr 1120(勃林格殷格翰公司)是一种新的口服抗血管生成药,抑制VEGF、PDGF、FGF等的作用,目前分别开展了治疗晚期卵巢癌和NSCLC的Ⅲ期临床研究。 Axitinib(辉瑞公司)作为一种口服、强效血管生成抑制剂,同时靶向c-kit、VEGFR-1/2/3和PDGFRβ。2007年12月,本品在美国获治疗甲状腺癌孤儿药身份。目前,正在进行治疗胰腺、甲状腺和肾癌的Ⅲ期试验。Ⅱ期临床研究显示,对一线治疗后失败的转移性肾癌患者仍有效,该药可缩小索拉非尼治疗无效患者的肾肿瘤。5.2 哺乳动物雷帕霉素靶蛋白抑制剂 哺乳动物雷帕霉素靶蛋白(mTOR)是一种Ser/Thr激酶,属于PIKK超家族,对调节细胞周期、蛋白质合成等具有重要作用,与多种肿瘤的发生、发展密切相关。mTOR已成为肿瘤治疗的热门靶点。第1个上市的mTOR抑制剂是Temsirolimus(惠氏公司),2007年通过美国FDA和EMEA批准用于治疗肾细胞癌。与常规的干扰素α或白细胞介素-2免疫疗法相比,该药单独治疗可延长总生存期、明显延长PFS,且耐受性更好。 依维莫司(Everolimus,诺华公司)是雷帕霉素的衍生物,哺乳动物雷帕霉素靶蛋白抑制剂,2009年通过美国FDA和EMEA的审批,用于晚期肾癌患者的二线治疗。 Ridaforolimus(默克公司/Ariad公司)为小分子mTOR抑制剂,针对治疗Trastuzumab抵抗性的转移性乳腺癌的Ⅱ期临床试验结果良好,针对Bevacizumab抵抗性的乳腺癌研究也完成受试者招募。针对转移性骨肉瘤的Ⅲ研究也于2008年正式启动。5.3 血管内皮细胞增殖抑制剂 恩度(Endostatin,烟台麦得津公司)是全球首个血管内皮抑制素药。通过抑制形成血管的内皮细胞的迁移来达到抑制肿瘤新生血管的生成,可阻滞肿瘤细胞的营养供给,从而达到抑制肿瘤增殖或转移目的。 考布他汀及其衍生物是一类微管破坏类药,通过发挥抑制内皮细胞有丝分裂和抗血管效应双重阻滞细胞周期中纺锤体的形成,减少肿瘤血管血流。目前,CombretastatinA-4phosphate(CA4P)正在甲状腺癌的Ⅲ期临床研究。 Vadimezan(Antisoma,诺华公司)被称为“破坏肿瘤血管制剂,可通过微管蛋白非依赖性机制选择性地阻滞肿瘤脉管系统,选择性地切断肿瘤供血,并最终导致肿瘤细胞死亡。该药联合卡铂、紫杉醇治疗NSCLC的Ⅱ期研究表明,总有效率为37.9%~46.7%,进展期为5.5个月,中位生存期为14.9个月。 ZD4054(阿斯利康公司)是目前最具潜力的强效特异性内皮素受体拮抗药,正开展激素抵抗前列腺癌的Ⅲ期临床研究。5.4 其它靶向抗肿瘤药 默克公司的Vorinostat(商品名:Zolinza)是世界上第1个组蛋白去乙酰化酶抑制剂(HDACI),另一个HDACI为Gloucester公司的Romidepsin(商品名:Istodax)。2药分别于2006、2009年被FDA批准上市用于皮肤T淋巴细胞瘤的治疗。 百时美施贵宝公司的Tanespimycin是第1个进入临床研究的热休克蛋白抑制剂(HSPI),目前已进入多发性骨髓瘤的Ⅱ/Ⅲ期临床研究。 已获得美国FDA快速审批资格的BSI-201(赛诺菲-安万特公司)是首个进入Ⅲ期临床试验的多聚ADP核糖聚合酶抑制剂,与吉西他滨和卡铂联合治疗三阴性转移性乳腺癌,耐受性良好,可将患者的中位生存时间由7.7个月延长至12.2个月。6 展望 近年来,全球抗肿瘤药研发取得了长足进步,在抗肿瘤药的研发领域异常活跃,在研药物类别多样,其中分子靶向抗肿瘤药的研发占主导地位。但仍需清楚地认识到:首先,肿瘤发病机制尚未完全阐明,抗肿瘤药单药疗效并未提高(<30%);其次,肿瘤耐药问题仍是目前l临床治疗失败的主要原因之一,新靶点的揭示和不同靶点药物联用,从一定程度上克服或延缓了耐药问题,但多药耐药性机制还有待于进一步明确;再次,与传统细胞毒药物相比,分子靶向抗肿瘤药的不良反应较少,但该类药的某些反应仍需引起关注,特别是皮肤反应、间质性肺疾病和心血管不良反应等特殊不良反应;最后,靶向抗肿瘤药长期应用带来的耐药问题和对机体的影响也值得探究。总体来看,随着肿瘤发生机制的逐步揭示,相信特异性针对肿瘤细胞的药物将不断上市,肿瘤患者的生存质量将显著提高,甚至长期带瘤生存也成为可能,肿瘤完全可能像糖尿病、高血压一样作为一种可控的慢性病,与机体长期和平共处。 来源:《中国药房》2010年4月第21卷第14期(由杨燕供稿)
肝性胸水是指无原发性心肺疾病的肝硬化失代偿期出现的单侧或双侧胸腔积液。肝性胸水可以与大量肝性腹水并存,也可仅有少量腹水或无腹水的情况下存在;与腹水并存时,大多数先出现腹水,而后出现胸水,也有的胸腹水同时出现。肝硬化胸水是肝硬化较为少见的并发症,但有潜在的危险性,愈后较差,死亡率较高。由于多数患者并有严重的肝功能障碍及代谢紊乱,治疗困难棘手,常因呼吸功能衰竭或严重缺氧而加重肝功能衰竭,最后导致死亡。肝性胸水85%位于右侧,13%位于左侧,2%位于双侧。女性患者多于男性患者,其发病机制目前尚不清楚。 现在认为与下列因素有关: 1、低蛋白血症:肝硬化患者因肝功能受损,则合成清蛋白障碍,造成低蛋白血症,引起血浆渗透压下降,使体液漏出到胸腔。 2、横隔局部缺损时腹腔体液直接经缺损部位进入胸腔:肝硬化病人失代偿期出现腹水,随着病情变化,进一步恶化,腹水不断增多,致使胸腔内压逐渐升高,使横隔腱部变薄,腱索分开,随后薄的浆膜内层凸向胸腔形成小泡,在咳嗽或用力时,腹腔内压力突然升高时,上述小泡由于压力突然作用发生破裂形成极小的横隔空隙。这就是腹腔内液体进入胸腔的理论基础。当吸气时,胸腔内为负压,腹腔内为正压,所以腹腔内液体通过这些小的裂孔,顺压力梯度被吸入胸腔。 一、临床表现 由于肝硬化和腹水的存在导致胸水病人一般具有肝硬化和腹水为主的两方面临床症状,少量胸水病人一般没有症状,中、大量胸水可出现不同程度的胸闷、呼吸困难、咳嗽等,约1/3病人可出现低热。呼吸系统症状随着胸水量逐渐增多而加重,缺氧导致呼吸衰竭。也有的症状突然加重,此时可能是横隔裂孔突然破裂增大导致大量腹水漏入胸腔。一般患者无明显胸痛,体检时可发现病人患测叩诊浊音,呼吸音减低或消失,X线检查呈现胸腔积液的表现。 二、检查方法 1、实验室检查:经穿刺吸取胸腔积液为漏出液,与一般腹水相似。但由于积液形成的机制不同,两者可略有差别,肝性胸水细胞数较低,而蛋白浓度较高。特点:中性粒细胞计数<0.25×109/L。蛋白定量<25g/L,胸水与血清总蛋白比值<0.5,乳酸脱氢酶比值<0.6,白蛋白比值>1.1,胆红素比值<0.6,PH值>7.4,胸水的葡萄糖与血糖浓度相似,淀粉酶较低,细菌培养为阴性,腹水癌细胞检查阴性,血性胸水罕见,血沉不快。 2、放射线检查:放射线核素扫描是证实腹水是否通过横隔而发生,为最安全、准确率较高的非侵入性检查,有的学者报导,其敏感性为71%,特异性为100%。有的学者提出,该方法有利于检查左侧胸水或无腹水的肝性胸水。 3、胸腔镜检查:大部分胸腔积液通过上述检查方法可以确诊,但对少数难以确诊的病人必要时要进行胸腔镜检查。该方法可以窥视整个胸膜腔观察病变的形态特征与分布范围,能发现特殊病变,还可以在直视下进行组织学活检,甚至需要时在电视辅助下行胸腔镜手术(VATS)。 三、诊断: 在肝硬化失代偿期患者出现胸腔积液,尤其是右侧,胸水性质为漏出液者均可诊断肝性胸水。但应该除外心肾疾病引起的胸腔积液,还有结核性疾患。当肝硬化和腹水治疗好转时,胸水症状不见好转或加重时,应该排除结核性胸膜或癌性胸水等。 四、治疗: 肝硬化胸水常常因为是进展性的或晚期肝硬化而被列为肝脏移植。 1、一般治疗:其治疗目标为减轻症状,防止并发症,等待肝移植。除原病的治疗外(包括卧床休息、保肝治疗、营养支持治疗、输入白蛋白、血浆和氨基酸等)。严格限盐,限定每天2g。利尿剂的应用是首要治疗的方法,利尿剂使用螺旋内酯和呋噻米联合使用,起始前者每天40mg,后者每天100mg。效果不明显可以调整剂量(剂量按4:10),注射剂量不宜过大,滴速不宜过快。另外尚可应用奥曲肽,特别加压素对肝性胸水有效。其机制是减少肝血流量,降低门外压,减少胸水的形成。 2、胸腔穿刺治疗:是有效的治疗方法。能立即缓解患者的呼吸困难,但不是一种长久治疗的方法。不能减少腹水的生成,而且首次大量抽液可致单侧肺水肿和低血压,反复抽液可造成大量的液体、蛋白质丢失,引起胸水量增多,恶性循环,且不利于横隔裂孔闭合。最初治疗不主张胸腔内持续引流的方法,因为可出现其它并发症与气胸、出血和感染等等。 3、经颈静脉肝内门体分流术(TIPS):肝硬化患者肝窦压力增高是腹水形成的主要原因,肝性胸水来自腹水,而TIPS是在肝内门静脉和肝静脉间建立一个分流通道以减轻门静脉压力,控制和减少腹水的产生,是治疗肝性胸水的一种有效方法。但也有其不足之处,短时间可引起肝性脑病和通道阻塞,因此近来应用带膜支架以改善其不足,已收到良好效果。使TIPS的应用更有前景,术后一年分流通道通畅率达84%。 4、外科治疗:包括化学性胸膜固定术、胸腔置管引流术、胸腔分流术和横隔裂孔修补术。需要提醒的是肝病临床医生要重视肝性胸水的产生,认真对患者进行全面体检,特别是失代偿肝硬化病人,不应在诊治肝病时,忽视了胸部的系统检查,漏掉肝性胸水的存在。
经皮肝穿胃冠状静脉栓塞术(percutaneous transhepatic varices embolization,PTVE)是经皮肤肝脏穿刺至肝内门静脉分支,选择性的进行胃冠状静脉插管,用栓塞材料栓塞食管胃底曲张静脉,达到治疗食管胃底曲张静脉出血的一种有效的介入性治疗方法。临床研究证实PTVE在治疗食管胃底静脉曲张出血,降低病死率等方面有明显疗效 门脉高压症时,胃底、食管下段交通支开放,门静脉血流经胃冠状静脉,通过食管胃底静脉与奇静脉、半奇静脉的分支吻合,流入上腔静脉。胃冠状静脉血流呈离肝血流,该离肝血流使得经导管注入的栓塞剂能够到达曲张的食管胃底静脉。栓塞剂注入静脉后可使内皮细胞损伤、脱落,内皮下胶原纤维暴露,激活内源凝血系统,致使管腔内混合血栓形成,曲张的食管胃底静脉闭合,最终达到止血目的。该项技术主要适应证为食管胃底静脉破裂大出血,内科保守治疗无效;大量失血,患者一般状况差,不能耐受急诊手术;或严重的食管胃底静脉曲张,近期有出血可能。 止血效果及对曲张静脉的影响 PTVE先用液体栓塞剂闭塞胃底食管曲张静脉再用钢圈永久性完全栓塞胃冠状静脉主干,彻底阻断门静脉和奇静脉之间的反常血流而达到迅速有效的止血目的,曲张静脉被完全阻断或血流量明显减少,降低再出血风险。黄桂芹等对50例肝硬化上消化道出血患者实行PTVE术,其中49例止血成功,3个月及6个月随诊,再出血发生,再出血发生率明显低于行常规药物治疗的对照组,且住院天数较对照组缩短。张建军等报道17例肝硬化门静脉高压症食管胃底静脉曲张破裂出血患者,行胃冠状静脉栓塞治疗,其中5例为急性上消化道大出血(出血量>1 000 ml),行急诊手术,17例患者术后均立即止血(100%),无手术死亡,术后造影胃冠状静脉内血流均完全阻断,术后1周X线检查15例曲张静脉完全阻断,2例不完全,仅少量血流,术后2周X线钡餐透视检查11例曲张静脉消失,6例曲张度下降。权启镇等报道32例肝硬化并食管胃底静脉曲张出血经内镜下套扎、硬化治疗后仍有出血的患者,经PTVE治疗后有29例得到随访,随访3~11个月,超过6个月者24例。24例术后1~3个月内行胃镜复查,5例6~10个月复查胃镜,显示胃底静脉曲张完全消失者21例,明显改善者8例。胡元明等观察30例行PTVE的患者的止血效果,27例得到随访,随访2~18个月,超过6个月者14例12个月者10例12例出血期间急诊栓塞治疗的患者术后即刻及1周内无继续出血表现,生命体征稳定,血红蛋白回升,1周左右大便颜色变黄,18例择期手术者术后无再出血,17例患者术后1~3个月内行胃镜复查,13例显示胃底曲张静脉完全消失,4例显著改善。PTVE术后再出血率各家报道不一致,有报道再出血率为27.20%~65.00%。崔屹等报道PTVE术后再出血率为10%,再出血间期较药物治疗组长,且与药物治疗比较,PTVE组出血病死率显著降低。综上所述PTVE在急诊止血、预防再出血、阻断或减少曲张静脉血流方面均有较好疗效。 对门静脉压力的影响 大多数学者认为行胃冠状静脉栓塞术后,由于曲张血管栓塞后门静脉血流重新分布,导致入肝门静脉血流量增加而使门静脉压力增高。国内相关研究亦证实PTVE术后,门静脉压力较术前增高,但门静脉管径及血流量没有显著改变。门静脉压力的增加有继续引发新的静脉曲张的可能,增加再出血的危险度,但对改善肝脏血流灌注是有益的。所以应正确看待此种压力变化,可联合行经颈静脉肝内门体分流术以克服这一不利因素。 对肝功能的影响 经皮肝穿胃冠状静脉栓塞术阻断了曲张的食管胃底静脉的血流,增加了门静脉压力,促进肝血流灌注,理论上有利于肝胞再生和有效改善肝脏功能。张希全等报道,37例肝硬化门静脉高压症急性上消化道大出血患者行经皮经肝穿刺门静脉栓塞后经过保肝、抗感染治疗,肝功能稳定或好转32例,占86%;肝功能减退5例,占14%。但大部分报道认为术前术后肝功能无明显变化。 并发症 门静脉压力增高,引发或加重门静脉高压性胃病:曲张的胃底食管静脉(丛)被栓塞后,一般在2周左右容易发生再出血,这与国内报道基本一致,可能是因为由于曲张的主要静脉被栓塞后,门静脉压力又发生变化(增高),新的侧支循环建立,引起小的静脉再次出血,但一般出血量较少。王青等报道5例消化道出血患者行PTVE后2周2例发生再出血,但出血量明显减少(大便潜血阳性)。权启镇等报道29例患者随访期再次出现上消化道出血者1例,占3.1%(1/29),胃镜检查显示原胃底静脉曲张明显改善,但伴广泛胃黏膜糜烂,给予制酸、胃黏膜保护剂等处理后止血,考虑为门静脉高压性胃黏膜病变。 其他不良反应 包括穿刺通道出血、栓塞剂反流、插管损伤导致门静脉血栓形成、异位栓塞(肺栓塞、脑栓塞)等,拔管前仔细阻塞穿刺通道,缓慢注射栓塞剂,仔细分析门体循环,一般都能避免。其他轻微并发症有发热、腹水渗漏等,应给予对症处理。 总结 总之,肝硬化引起的胃底食管静脉曲张有多种治疗方法,但均有各自的缺点。经胃镜下注射硬化剂治疗因其较难充分闭塞所有曲张静脉尤其是胃底曲张静脉而疗效欠佳,特别是经过硬化剂治疗后,随着门静脉压力的升高,胃底静脉曲张会更加明显。胃底静脉离断术或门腔静脉分流术或经颈静脉肝内门腔静脉分流术治疗亦可降低门脉压,减少出血,亦因患者肝功能差、诱发肝性脑病等原因使其临床应用受到很大限制。经皮肝穿胃冠状静脉栓塞术紧急止血是一种安全有效易操作的方法,属于介入断流术,止血效果肯定,同时断流术增加了门静脉压力,促进肝血流灌注,有利于肝胞再生和有效改善肝脏功能。虽然Lunderquist 1974年报道了经皮食管胃底静脉栓塞术,但该技术在国内并未得到推广应用,既往认为该方法操作复杂,成功率低,术后再出血发生率高。随着介入放射学技术的不断成熟,经皮门静脉穿刺插管成功率高;DSA的普及使得对门静脉系统的血流动力学研究及侧支血管的观察更加容易和客观,近年来经胃肾静脉分流通道行胃底静脉栓塞术避免对肝脏的穿刺损伤;可联合TIPSS术治疗门静脉高压症;经皮食管胃底静脉栓塞和部分性脾栓塞联合应用具有止血和降低门静脉压力的双重作用,该领域有待于进一步的研究及探索。
Post–Transjugular Intrahepatic Portosystemic Shunt Follow-Up and Management in the VIATORR Era VIATORR-TIPS术后随访和管理策略Introduction简介The transjugular intrahepatic portosystemic shunt (TIPS) is a non–selective portosystemic shunt created using endovascular techniques. The first TIPS was performed in Freiburg, Germany in 1988 by Richter et al; Since its inception after 27 years, the TIPS procedure has gained a place as a therapeutic option in the management of complicated portal hypertension.经颈静脉肝内门体分流术(TIPS)是一种非选择性门体分流术,采用血管内介入技术完成。第一例临床TIPS于1988年由Richter等人在德国弗赖堡完成;诞生27年来,TIPS在复杂的门静脉高压症治疗中获得一席之地。The first endovascular stent used in the creation of a TIPS procedure was the balloon-expandable Palmaz stent (Cordis Corporation, Miami Lakes, FL). Once the procedure became widespread, the Wallstent self-expandable stent (Boston Scientific, Natick, MS) became the preferred stent because of its flexibility, range of lengths and diameters, and ease of use. The Wallstent was the first endovascular stent to be approved by the Food and Drug Administration (FDA) for a TIPS application. Thousands of TIPS procedures were successfully completed with the Wallstent endoprosthesis; however, one of the major problems encountered with the use of the Wallstent was the development of a thick pseudointimal hyperplasia, which resulted in poor patency rates. The thick intimal hyperplasia was caused by bile leaks into the shunt lumen. Poor shunt patency rates has always been considered to be the “Achilles tendon” of TIPS and the development of stent grafts was the next logical step to attempt improvement of patency rates.第一个TIPS支架是球囊扩张式的Palmaz支架(Cordis Corporation, Miami Lakes, FL)。当技术推广开来,WELLstent自膨胀支架(Boston Scientific, Natick, MS)以其其柔顺型、长度和直径的范围和易于操作等特点而成为首选支架。Wallstent是第一个被美国食品和药物管理局(FDA)批准用于TIPS适应症的血管内支架,成千上万的TIPS手术使用了Wallstent支架;该支架置入后主要问题是厚的假内膜增生,导致通畅率很低。厚的内膜增生是由于胆汁漏入肝实质内的人工分流道所致,低分流通畅率一直被认为是TIPS的“阿喀琉斯之踵”,而覆膜支架的研发是试图提高通畅率的下一个合乎逻辑的举措。The VIATORR self-expandable polytetrafluoroethylene (PTFE) covered stent-graft (WL Gore, Flagstaff AZ) was approved by the FDA for a TIPS application in December of 2004.10Recent publications have established that shunt efficacy, patency rates, and survival in high-risk patients may be better when the TIPS is created with the VIATORR stent grafts compared with bare stents. The aim of this article is to present an overview of the follow-up and clinical management of patients who have undergone a TIPS procedure with VIATORR stent grafts. The 2 major indications for a TIPS procedure remain the management of variceal bleeding and the treatment of ascites. The postprocedural care of patients with these 2 problems will be addressed.2004年12月,美国食品及药物管理局(FDA)批准了VIATORR自膨式聚四氟乙烯(PTFE)覆膜支架(WL-Gore,Flagstaff AZ)的TIPS适应症。最近已发表的研究证实,使用VIATORR覆膜支架执行TIPS时,高危患者的分流效率、通畅率和存活率与裸支架相比可能会更好,本文对应用viatorr支架行TIPS术患者的随访和临床管理进行综述。TIPS手术的两个主要适应症仍然是静脉曲张破裂出血和顽固性腹水的治疗,这两类患者的TIPS术后随访和管理本文将详细阐述。Device Description and Placement Technique 支架参数详述和使用技巧Before discussing the clinical management of patients undergoing a TIPS procedure with the VIATORR stentgraft, it is pertinent to briefly review the stent design and placement technique.在讨论使用VIATORR支架进行TIPS手术的患者临床管理之前,有必要简要回顾下支架设计理念和放置技巧。The VIATORR stent-graft is the first dedicated stentgraft system specifically designed for a TIPS application. It was designed to improve the patency of TIPS. This stentgraft system received approval by the FDA for the TIPS application in 2004. The VIATORR can be considered to be a “hybrid” stent graft system. It is a nitinol, selfexpandable stent graft with an uncovered segment of 2 cm in its leading end and a thin, bile resistant, double, e-PTFE layer of varying lengths in its trailing segment. The interface between the covered and noncovered segments is marked by a radiopaque gold band. The diameters of the stent-graft system range between 8 and 12 mm and the lengths of the covered segment range between 4 and 8 cm. The stent-graft system has an excellent radial force and hoop-strength; it is flexible enough to take the sharp curves sometimes encountered during creation of these shunts, making it an ideal system to be inserted within the hard, cirrhotic liver.VIATORR支架是第一个专门为TIPS设计的覆膜支架系统。这种支架系统在2004年获得了FDA对TIPS适应症应用的批准。这是一种镍钛合金自膨胀支架,其前端有2厘米的裸段,其尾端有一层长度不等的薄的、抗胆汁的双e-PTFE层。覆膜段与非覆膜段之间的界面有一条不透光的金带。支架直径在8-12毫米之间,覆膜段的长度在4-8厘米之间。支架具有良好的径向支撑力和适应弯曲的能力;它足够灵活,能够适应甚至锐角的分流道,使其成为硬化肝脏内植入的理想分流系统。From the technical standpoint, the deployment of a VIATORR stent-graft is somewhat more complicated than the deployment of a bare stent. First of all, a 10 FR, sheath needs to be advanced into the main portal vein to ensure proper stent-graft deployment, a maneuver that may be technically difficult when the angle of entry into the portal vein is too acute. Tract length calculation is the next critical step. A direct portogram using a measuring catheter should always be performed before deciding the optimal VIATORR stent-graft length to be used (Fig. 1). The ideal location of the trailing end of the stent graft is at the junction of the selected hepatic vein and the inferior vena cava or in the hepatic vein within 1 cm of the junction with the inferior vena cava (Fig. 2). Suboptimal stent-graft length may result in decreased patency rates.从技术角度来看,与裸支架相比Viatorr支架的置入要复杂得多。首先,需要将10FR的鞘推进到门静脉主干,以确保覆膜支架的成功置入,当穿刺套件进入门静脉的角度与主干太小时,推进长鞘将在技术上存在难度。穿刺道长度计算是第二个重要步骤,在确定最佳的Viatorr支架长度之前,应始终使用测量导管进行直接门静脉造影(图1)。支架末端的理想位置是在所选肝静脉和下腔静脉的交界处,或在与下腔静脉交界处1cm内的肝静脉(图2)。不理想的支架长度可能导致通畅率降低。图1. Viatorr支架的经颈静脉肝内门体分流术(TIPS)术中获得的带标记导管的数字减影门静脉造影(DSA)图像。白色箭头标记进入门静脉的位置和肝静脉与下腔静脉的交界处。总共两个箭头之间有7个标记段,所以在这个分流术中使用的支架的正确长度是8厘米。图2. 完成TIPS后获得的数字减影直接门静脉图。注意支架的尾端位于肝静脉和下腔静脉的交界处,这是支架尾端的理想位置。Imaging and Follow-Up Interventions: VIATORR TIPSViatorr-TIPS的影像学和随访干预Frequent non–invasive shunt surveillance of TIPS created with bare stents was extremely important because of the early failure rate and poor primary patency rates observed with these shunts. Patients undergoing TIPS with bare stents usually underwent a Doppler ultrasound to assess shunt patency within 24 hours of completion of the procedure. This “early” ultrasound assessment of the shunt was helpful because if shunt abnormalities were detected, including poor flows or occlusion, this prompted an immediate TIPS revision. 对应用裸支架的TIPS进行频繁的分流道无创监测非常重要,因为早期的分流失败率高和初次通畅率很低。接受裸支架TIPS的患者通常在手术完成后24小时内接受多普勒超声评估分流通畅性。这种“早期”超声对分流的评估是有帮助的,因为如果发现分流异常,包括血流不畅或闭塞,会促使立即行修正术。Ultrasound assessment of the VIATORR stent-graft within 24 hours of shunt creation is not recommended because proper insonation of the VIATORR is impeded by a thin layer of air, which is trapped between the 2 e-PTFE layers of the stent-graft, often yielding false-positive studies suggesting shunt occlusion. At our Institution, the baseline ultrasound assessment of patients who have undergone a TIPS procedure with a VIATORR is usually performed 5-10 days after the procedure. TIPS created with VIATORR stent grafts have better patency rates than shunts created with bare stents. Shunt failure rates and postprocedural interventions are significantly lower for properly created shunts with VIATORR stent grafts when compared with bare stents (Fig.3). Frequent periodic surveillance and shunt revision procedures in VIATORR created shunts are not usually necessary.不建议在分流术后24小时内对viatorr支架进行超声评估,因为声波受到两个e-PTFE膜之间一层薄薄的空气的阻碍,常常产生假阳性结果提示分流道阻塞。在我们中心,使用viatorr进行TIPS术的患者的基线超声评估通常在术后5-10天进行。与裸支架TIPS分流相比,用viatorr支架的TIPS分流具有更好的通畅率。与裸支架相比,用viatorr支架的TIPS分流失败率和术后干预显著降低(图3)。Viatorr-TIPS不必频繁进行超声监测和修正。图3.(A)年轻暴发性布加综合征患者Viatorr-TIPS后获得的直接门静脉造影,支架通畅良好,手术于2005年3月完成。(B) 2009年10月,在分流4年半后复查的直接门静脉造影,支架仍通畅良好。因监测多普勒显示分流速度低才行有创直接门脉造影复查,病人无症状,病人不需要任何干预。In our opinion, it is reasonable to perform ultrasound surveillance of VIATORR created shunts every 6-12 months, depending on patient compliance and clinical condition. Previously described flow velocity parameters for functioning and failing shunts created with bare stents are slightly different to TIPS created with VIATORR stent grafts. Recent studies show that mean shunt flow velocities of less than 90 cm/s or higher than 200 cm/s are considered to be abnormal in shunts created with VIATORR stent grafts. Regarding the main portal vein velocity; a value lower than 30 cm/s was found to be highly specific for VIATORR shunt dysfunction. These are useful parameters that can be applied in daily clinical practice and if detected, should warrant invasive shunt revision (Fig. 4).我们认为,根据患者的依从性和临床情况,每6-12个月进行一次VIATORR分流道超声监测是合理的。先前描述的裸支架形成的通畅分流和失败分流的流速参数与Viatorr支架TIPS稍有不同。最近的研究表明,平均分流速度小于90cm/s或大于200cm/s被认为是viatorr支架分流异常的表现;低于30cm/s的数值对Viatorr分流道失功能具有高度特异性。这些参数在日常临床实践中是有用的,如果被检测到,则应进行有创性分流道修正(图4)图4.(A)治疗顽固性腹水的viatorr-TIPS术后10天的基线彩色多普勒图像显示分流道门静脉末端内的流速峰值为108.3cm/s,在正常范围内。这表明分流道通畅,功能良好。(B) 治疗顽固性腹水的TIPS术后10天的基线彩色多普勒图像显示分流道肝静脉末端的流速峰值为170.9cm/s,在正常范围内,表明分流道通畅,功能良好。(图的彩色版本可在线获得)Postprocedural Care: Patients With Gastrointestinal Bleeding消化道出血患者术后管理Immediate Patient Care After an Emergency TIPS急诊TIPS术后即刻的管理Patients who undergo an “Emergency TIPS” are usually unstable and critically ill and for this reason are at risk of having a poor postprocedural outcome. Most of these patients are brought to the angiography suite directly either from the emergency department or the intensive care unit, usually after acute resuscitation efforts have been started. Most of the patients who undergo an emergency TIPS are managed with vasoactive drugs to control the bleeding (terlipressin, somatostatin, or octreotide), prophylactic antibiotics, resuscitation with IV fluids, transfusions, and intubated. These patients usually return to the intensive care unit immediately after the procedure.接受“急诊TIPS”的患者通常生命体征不稳定,病情危重,因此有可能术后效果不佳。大多数患者在紧急复苏后直接从急诊室或重症监护室(ICU)被转运到血管造影室(介入手术室)。接受急诊TIPS的大多数患者都使用血管活性药物来控制出血(特利加压素、生长抑素或奥曲肽)、预防性抗生素、静脉输液复苏、输血和插管等,这些患者术后通常再转回ICU。Patient care in the intensive care unit immediately after emergency TIPS focuses on maintaining vital signs stable, following clinical parameters to determine if bleeding has been controlled, monitoring hepatic, renal, cardiac, and respiratory function and managing encephalopathy. Monitoring of liver function at this time is essential as these patients are at higher risk of developing liver failure after the procedure. Signs of liver function deterioration usually appear within the first 48 hours and usually manifested by elevation of the serum bilirubin, liver enzymes, and altered mental status. Management is usually supportive. Liver decompensation after a TIPS is probably related to a suboptimal hepatic arterial response after the portal venous flow diversion resulting from a successful shunt creation. In patients who survive, there is typically a mild-to-moderate elevation of serum bilirubin and liver enzymes that reaches a plateau at 7-10 days, remains stable for 5-6 days and then progressively decreases back to either normal or baseline levels. Patients who undergo emergency TIPS and have progressive deterioration of liver function are usually patients with high Child-Pugh scores (Class C with scores higher than 12) and high APACHE II scores (higher than 18) and have very poor prognosis, reaching an early, 30-day mortality rate of 98%100%. TIPS reduction or occlusion is usually not indicated in these stages. Interestingly, patients who show progressive deterioration and die after emergency TIPS, usually do not die of recurrent or persistent bleeding; the cause of death is predominantly multi-organ failure. The patients who have persistent bleeding after an emergency TIPS require emergency shunt revision with pressure measurements, further dilatation of the shunt, variceal embolization, or embolization of high-flow portosystemic shunts.急诊TIPS后,重症监护室的患者管理重点是维持生命体征稳定,根据临床参数判断出血是否得到控制,监测肝、肾、心和呼吸功能,以及预防(或治疗)肝性脑病。此时监测肝功能是必要的,因为这些患者在手术后有更高的肝衰竭风险。肝功能恶化的迹象通常在48小时内出现,通常表现为血清总胆红素、肝酶升高和精神状态的改变。围术期治疗通常是支持性治疗,TIPS后的肝功能失代偿可能与成功分流导致的门静脉血流改道后肝动脉尚未来得及代偿有关。在存活的患者中,血清总胆红素和肝酶通常在7-10天达到稳定水平,5-6天内保持稳定然后逐渐减少到正常水平或基线水平。接受急诊TIPS肝功能进行性恶化的患者多为Child-Pugh评分高(C类,评分高于12分)、APACHE II评分高(评分高于18分)、预后极差的患者,前30天死亡率达98%- 100%。在这些阶段通常没有TIPS分流减少或分流道闭塞的迹象。有趣的是在急诊TIPS后出现病情进行性恶化并死亡的患者,通常不是死于复发性或持续性出血,死亡的原因主要是多器官功能衰竭。急诊TIPS术后持续出血的患者需要再测量压力、必要时进一步扩张分流道、栓塞曲张静脉或栓塞高流量门体侧枝等。Patients who stabilize and survive the acute insult are usually sent to a regular unit and then subsequently discharged. The baseline ultrasound assessment of the shunt is usually obtained 5-10 days after the procedure. 病情稳定并在急性灾难性打击中存活下来的患者通常会被送往普通病房,之后在那出院,分流道的基线超声评估通常在术后5-10天进行。Immediate Patient Care After Elective TIPSTIPS术后的即刻护理Patients who undergo an elective TIPS are quite different. These patients are usually stable before the procedure and have been carefully evaluated before intervention.接受TIPS的患者病情各不相同。这些病人在术前通常是稳定的,并在治疗前经过仔细评估。At our institution, these patients are admitted over- night for observation after the procedure. Immediate postprocedural care includes a clinical evaluation and liver function tests within 24 hours after the procedure. If a signicant abnormality of the liver function is detected or if the patient is doing poorly after the procedure, the patient is kept in the hospital for further monitoring. If all laboratory work-up is within normal limits and the patient is doing clinically well, the patient is discharged. All patients are discharged with dietary instructions, prophylaxis for encephalopathy and an appointment to return in 7-10 days. The 7-10 day follow-up visit after an elective TIPS includes a clinical evaluation of the patient's condition, assessment of mental status, repeat liver function tests, and a baseline ultrasound assessment of the shunt. Adjustments to medical management are conducted during this visit and if the patient shows signs of clinical liver failure and abnormal liver function tests, they are admitted for management of liver failure after TIPS.在我们的中心,这些病人在手术后住院观察。术后即刻护理包括术后24小时内的临床评估和肝功能化验。如果发现明显的肝功能异常或者术后一般情况较差,病人就会留在医院接受进一步的监护。如果所有的实验室检查都在正常范围内,并且病人的一般情况良好,才可出院。所有出院的病人都经过饮食指导、脑病预防教育,然后预约出院后7-10天回访。TIPS术后7-10天的随访包括对患者病情的临床评估、精神状态评估、复查肝功能和对分流道的基线超声评估。访视期间对口服药剂量进行调整,如有临床肝功能衰竭迹象及肝功能检测异常,应再入院进行抗肝功能衰竭治疗。Long-Term Care After TIPS Created With VIATORR Stent- Graft: BleedingViatorr-TIPS术后针对再出血的长期随访内容At our Institution, the long-term follow-up of patients who have undergone a TIPS procedure for a bleeding indication is similar whether the TIPS was placed on an emergency basis or electively. Patients are followed in the outpatient setting by the Hepatologist and Interventional Radiologist. A Doppler ultrasound evaluation of the shunt is performed at 6-month intervals. If compliant with their visits, the patients are seen every 6 months and the nutritional status, liver function, kidney function, encephalopathy, and functional status are evaluated. Follow-up endoscopies are not rou- tinely performed provided that the portosystemic gradient after the procedure was lower than 12 mm Hg and that TIPS patency has been documented by Doppler ultrasound.在我们的中心,无论急诊TIPS还是平诊TIPS,术后访视内容是相似的。患者在门诊由肝病科医生和介入放射科医生随访。每隔6个月对分流道进行一次多普勒超声检查。对于依从性好的患者随访包括,病人每6个月访视一次,并评估营养状况、肝功能、肾功能、脑病和体能状态。术后门体压力梯度低于12mmhg,并且多普勒超声证实分流道血流通畅的患者,内镜检查不作为常规随访检查项目。Long-Term Care After TIPS Created With VIATORR Stent- Graft: AscitesViatorr-TIPS术后针对腹水的长期随访The management of patients with ascites is more complex than patients who had a bleeding episode and require closer, more dedicated follow-up care after the procedure. The development of ascites is a sign of poor prognosis; patients with ascites have a complex derangement of hormonal, electrolyte, kidney, and liver function; sometimes it is quite difcult to nd the correct balance to control the problem of ascites accumulation. This is further complicated by poor compliance, which is a frequent problem in this patient population.腹水患者的处理比出血的患者更复杂,而且在术后需要更密切、更专注的随访。腹水的发展是不良预后的标志;腹水患者存在激素、电解质、肾脏和肝功能的复杂紊乱;有时很难找到准确的平衡来控制腹水。因患者依从性差使得问题进一步复杂化,这也是这个病人群体中一个常见的问题。TIPS procedures performed to manage ascites are never performed on an emergency basis. Most times, both the referring physician and interventional radiologist have plenty of time to make a therapeutic decision and patients who undergo TIPS to control ascites usually have met certain criteria including (1) a diagnosis of refractory ascites, (2)diuretic nonresponsiveness or, (3)development of diuretic-related complications. Successful TIPS insertion in a patient with ascites has profound benecial effects including volume shifts from the splanchnic circu- lation to the central circulation, activation of the sodium natriuretic factor, and increasing sodium excretion. The proper creation of TIPS with VIATORR stent grafts with dedicated attention to optimal stent-graft positioning has improved outcomes mainly because of the predictable patency and decreased need for TIPS revision interventions.处理腹水从来没有在紧急情况下进行的,多数是内科医生和介入放射科医生有足够的时间来做治疗决定,病人接受TIPS来控制腹水通常满足某些标准:(1)难治性腹水(2)利尿剂抵抗(3)利尿剂相关并发症。成功的TIPS对病人腹水控制有深远的有益影响,包括体液从门静脉系统到体循环,激活利钠因子,并增加钠的排泄。因为Viatorr支架的高通畅性,低翻修率,合理的viatorr-TIPS改善了顽固性腹水的治疗结局。Approximately 80% of patients who undergo a TIPS procedure for the management of ascites improves their condition but require to maintain a low-sodium diet and must continue taking diuretics to achieve the treatment goal, elimination of the free intra-peritoneal uid.大约80%的患者接受了TIPS来治疗顽固性腹水,他们的情况有所改善,但仍需要保持低钠饮食,并必须继续服用利尿剂以达到消除游离在腹膜腔内液体的目标。Nutritional Aspects营养方面Malnutrition is common in the cirrhotic patient. Nutri- tional problems are related to inadequate nutrient intake because of nausea, early satiety, encephalopathy, and anorexia, abnormalities of carbohydrate, lipid, and protein metabolism, malabsorption, impaired liver capacity to store nutrients, and iatrogenic factors such as overzealous dietary restrictions, paracentesis, lactulose therapy, and frequent compulsory starvation. Patients who have undergone a TIPS procedure, especially those patients with ascites, face a triple burden of malnutrition charac- terized by changes in adiposity, skeletal muscle mass, and abnormalities in uid homeostasis and compartmentalization. There is no standardized approach to diagnose and classify malnutrition in these patients, and there is no general agreement on the criteria for when or how to implement nutritional intervention. Nutritional status diagnosis is based on a combination of methods such as subjective global assessment (Royal Free Hospital Global Assesment), mid arm-muscle circumference, skin-fold thickness, handgrip strength (dynamometry), dual energy X-ray absorptiometry, or air plethysmography along with details of dietary intake. Variables such as percentage ideal body weight, waist circumference, or plasma albumin cannot be used in this patient population because of the potential confounding effects of uid retention and the changes in protein metabolism, and tools such as bioelec- trical impedance provide unreliable estimates of nutri- tional status when used in an isolated fashion. Owing to the presence of ascites, the calculation of energy and protein requirements has to be done with either dry weight or ideal body weight., For well-compensated patients, 25- 35 kcal/kg/d of energy is appropriate. Malnourished patients may require 30–40 kcal/kg/d to promote anabo- lism. Dietary protein restriction should be avoided in this patient population except for very short periods in patients with gastrointestinal bleeding or acute encephalop- athy, 0.6-0.8 5 g/kg/day, taking into account the source of dietary nitrogen (ratio of 60:40 of protein vegetal or animal) and encouraging the patient to take as high a percentage of vegetable protein as possible. A range of 25%-30% of calories from fat is generally recommended. Patients should avoid fasting for longer than 3-5 hours during the day; they should be encouraged to take small and frequent meals distributed throughout the day (encourage eating foods which are calorie dense, high in ber, and contain protein). In addition, a late-evening snack is recom- mended for a more efcacious effect on substrate utilization. The optimal formulation for the late-evening snack it's not well established, but evidence suggests that it should contain at least 50 g of complex carbohydrate and or branched-chain amino acids. Branched-chain amino- acid supplementation during the day can be used also in patients with encephalopathy, patients eating less than 40 g of protein daily, or patients who are protein-intolerant. Fluid consumption should not exceed 1-1.5 L/d (including water from food) if there is coexistence of ascites and signicant hyponatremia. Fluid restriction is controversial and is not recommended for those patients with ascites who are hypovolemic or have only mild-to-moderate hypona- tremia (serum sodium Z 130 mEq/L). For patients with serum sodium lower than 130 mEq/L, an attempt is made to reduce dietary sodium intake to a minimum, ideally to an amount that is no greater than the patient's 24 hour urinary sodium excretion. However, this is difcult to achieve in the real-life outpatient setting. In our clinical practice, we ask patients to avoid any added salt in their diets, and to avoid food components that are known to be high in salt content. We advise patients to weigh themselves on a daily basis, and to contact us if their weight uctuates by more than 5 lb, or if they develop worsening ascites or edema.营养不良在肝硬化患者中很常见。营养问题与因恶心、早饱、肝性脑病、厌食、碳水化合物、脂质和蛋白质代谢异常、吸收不良、肝脏储存营养的能力受损、饮食限制、腹水穿刺引流、乳果糖治疗和频繁的强制饥饿等医源性因素引起的营养摄入不足有关。接受TIPS手术的患者,尤其是顽固性腹水患者,面临营养不良的三重负担,其特征是肥胖、骨骼肌质量的改变,以及液体内环境平衡和分布的异常。在这些患者中没有诊断和分类营养不良的标准化方法,也没有关于何时或如何实施营养干预的标准或普遍共识。营养状况诊断是基于多种方法的结合,如主观的整体评估(皇家自由医院全球评估),臂中部肌肉周长,皮肤褶皱厚度,握力(测力法),双能x射线吸收法,或空气体积描记法以及饮食摄入的细节。由于液体潴留的潜在干扰和蛋白质代谢的变化以及在孤立病例中生物电阻抗等工具提供不可靠的营养状况评估,比例变量如理想体重,腰围,或血浆白蛋白不能用于这类病人。由于腹水的存在,能量和蛋白质需求的计算必须以净体重或理想体重进行。对于代偿良好的患者,25-35千卡/公斤/天的能量是适当的,营养不良的患者可能需要30-40千卡/公斤/天来促进合成代谢。除了消化道出血或急性脑病短期限制膳食蛋白质外,其余此类病人都应该避免这样做。考虑到膳食来源0.6-0.85克/公斤/天的氮(植物蛋白和动物的比例为60:40),要鼓励病人尽可能高植物蛋白的比例。一般建议从脂肪中摄入25%-30%的热量,病人应该避免一天中禁食超过3-5小时;应该鼓励他们每天少吃多餐(鼓励吃高热量、高纤维、富含蛋白质的食物)。此外,为了更有效地利用底物,推荐晚间进行加餐。它的最佳配方还不是很确定,但有证据表明,它应该包含至少50克的复杂碳水化合物和或支链氨基酸。白天补充支链氨基酸也可用于脑病患者以及每天蛋白质摄入少于40克的患者或蛋白质不耐受的患者。如果同时伴有腹水和明显的低钠血症,液体入量不应超过1-1.5 L/d(包括来自食物的水)。液体限制是有争议的,不建议那些低血容量并腹水或只有轻度至中度低钠血症(血清钠≥130mEq/L)的患者进行液体限制。对于血清钠低于130mEq/L的患者(稀释性低钠血症),尝试将饮食中的钠摄入量降至最低,最理想的是不超过患者24小时尿钠排泄量。然而,这在现实的门诊环境中很难实现。在我们的临床实践中,我们要求患者避免在他们的饮食中添加任何盐,并避免已知的高盐食物。我们建议患者每天称一次体重,如果体重波动超过5磅(1磅等于453.592 37克)或出现腹水或水肿加重时要与我们联系。There is little information on energy or protein requirements in overweight and obese patients who undergo a TIPS procedure, thus generic recommendations should be applied. Weight loss should be encouraged with a bal- anced diet together with an increase in physical activity. In patients with obesity and decompensated cirrhosis, the best approach to reduce weight by reducing the carbohy- drate and fat content of the diet while maintaining a high protein diet. Deciencies of micronutrients are not easily assessed, but they are usually present especially of zinc, pyridoxine, thiamine, or vitamin B12, and fat-soluble vitamins (A, D, E, and, K). Oral replacement with vitamin D2 or D3 at 2000 IU/daily is generally adequate along with 1200-1500 mg/d of calcium. Multivitamin supplementa- tion is cheap and generally free of side-effects.很少有关于超重和肥胖患者接受TIPS的能量或蛋白质需求的信息,因此应该采用通用的做法。减肥应该鼓励平衡饮食并且增加锻炼,对于肥胖和失代偿肝硬化患者,最好的减肥方法是在保持高蛋白饮食的同时减少饮食中的碳水化合物和脂肪含量。微量元素特别是锌、吡哆醇、硫胺素、维生素B12和脂溶性维生素(A、D、E和K)的缺乏不容易评估,但微量元素缺乏的现象普遍存在。维生素D2或D3,每天2000iu,与1200-1500毫克/天的钙同时服用是比较合适的搭配,补充多种维生素很便宜,一般也没有副作用。Diuretics利尿剂Diuretic management in patients with large volume ascites may be difcult to regulate. These patients are usually started using an aldosterone antagonist acting at the distal convoluted renal tubule such as spironolactone and a loop diuretic such as furosemide. Patients are typically started on doses of 20-40 mg of furosemide and 50-100 mg of spironolactone. These doses can be progressively increased in 3 day intervals if there is no detectable improvement in the patient's condition to maximal doses of 400 mg/d of spironolactone and 160 mg/d of furosemide while watching serum electrolytes and kidney function on a weekly basis.对大量腹水患者的利尿剂治疗可能难以奏效,这些患者通常开始使用醛固酮拮抗剂作用于远曲小管(如螺内酯)和髓袢(如速尿)。起始剂量通常是20-40毫克速尿和50-100毫克螺内酯联合使用,利尿药剂量可以在患者治疗效果不好时每3天做一次调整,最大剂量为400毫克/天的螺内酯和160毫克/天的速尿,同时每周监测血清电解质和肾功能。After a successful TIPS procedure, the doses of diuretics are modied according to response. There is no denite rule on how to regulate diuretic doses after a successful TIPS; however, most patients require low doses of diuretics to achieve control of uid accumulation. Regarding the timing, patients who respond may show improvement as soon as 1 week after the procedure. In our practice, we discharge patients who underwent TIPS placement for ascites on low doses of diuretics, (furosemide =20 mg/d and spironolactone= 50 mg/d) with weekly follow-up monitoring of electrolytes and kidney function and clinic visits as needed. The majority of patients can be successfully weaned of all diuretics within 4-6 weeks following successful TIPS creation.TIPS术后,应根据患者情况调整利尿剂的剂量,至于如何调整尚无明确规定;然而,大多数患者仍需要低剂量的利尿剂来控制腹腔积液。从时间上来看,有反应的病人可能在术后一周就有改善。在我们的临床实践中,出院患者建议口服低剂量的利尿剂控制腹水(呋塞米20 mg/d和安体舒50 mg/d),每周随访监测电解质和肾功能和必要时门诊复诊。TIPS术后大多数患者可以在4-6周内成功停掉所有利尿剂。Management of Encephalopathy肝性脑病的管理Encephalopathy after TIPS is seen in approximately 20%- 30% of patients. Most patients develop stage I or II encephalopathy after TIPS and only a minority develop stages III or IV. The incidence of encephalopathy is comparable after the insertion of a covered stent or a bare stent. Only about 3%-7% of patients undergoing a TIPS procedure develop intractable encephalopathy and require a shunt reduction or occlusion. Prophylactic manage-ment for all patients undergoing a TIPS procedure is debatable as only about 30% of patients develop post- TIPS encephalopathy. Prevention of post-TIPS encephalopathy was evaluated in a small, prospective study and neither lactulose nor rifaximin were superior to placebo. TIPS术后脑病发病率约占20%- 30%,大多数为I期或II期脑病,只有少数患者发展到III期或IV期。在植入覆膜支架或裸支架后脑病的发生率相当,接受TIPS术的患者中,只有3%-7%的患者发展为顽固性脑病,这时需要缩窄分流道或闭塞分流道。对所有接受TIPS术的患者给予肝性脑病预防措施是有争议的,因为只有大约30%的患者在TIPS术后出现脑病。在一项小的前瞻性研究中对tips术后脑病的预防进行了评估,乳果糖和利福昔明均未优于安慰剂。At our Institution, all patients undergoing a TIPS procedure are discharged with a prophylactic regimen for encephalopathy. Our initial regimen typically consists of lactulose monotherapy, with the daily dose being titrated to achieve 2-3 soft but not diarrheal stools daily. We typically start with doses of 15 g by mouth, 3 times daily (eg, 10 cc of a 15 mg/10 cc solution 3 times daily). Since the day-to-day dose requirements vary for most patients, we avoid xed dosage regimens, and instead educate patients and their caregivers to adjust the amounts and frequency of lactulose as needed to achieve the desired laxative effect.在我们中心,所有接受TIPS术的患者出院都接受预防性脑病治疗。我们的初始治疗方案通常包括乳果糖单药治疗,每日剂量使达到2-3软便(不是腹泻性)的目的。我们通常从15克开始,每天3次(例如,10毫升的15毫克/10毫升溶液,每天3次),由于大多数患者每天的剂量要求不同,我们避免固定的剂量方案,而是教育患者和他们的护理人员根据需要调整乳果糖的量和频率,以达到预期的通便效果。The addition of rifaximin to our armamentarium has greatly improved the clinical outcomes of hepatic encephalopathy (HE). The benecial effect of adding oral rifaximin at a dose of 550 mg twice a day to standard lactulose treatment was rst documented by Bass et al. in 2010. The drug was approved by the FDA for treatment of HE in the same year. Several subsequent studies have conrmed the efcacy of this approach. There are lingering concerns over the long-term safety of rifaximin, related to a potentially increased risk for Clostridium difcile colitis, systemic fungal infections, or antibiotic resistance. How- ever, a recent systematic review demonstrated no signicant associations of rifaximin therapy with these adverse events. Therefore, we have a low threshold of adding rifaximin to standard lactulose depending on the patient's clinical status. Owing to its high price, we frequently engage the manufacturer's assistance program to procure the medication for patients with health insurance issues.在我们的用药目录中加入利福昔明大大改善了肝性脑病(HE)的临床结果。Bass等在2010年首次记录了在标准乳果糖治疗基础上联合使用每日两次、每次550 mg的口服利福昔明结果是有益的。同年,该药被FDA批准用于治疗肝性脑病,随后的几项研究也证实了这种疗法的有效性。人们对利福昔明的长期安全性仍存在担忧,因为它可能增加难辨梭状芽胞杆菌结肠炎、全身真菌感染和抗生素耐药性的风险。然而,最近的一项系统综述表明利福昔明治疗与这些不良事件没有显著的相关性。因此,根据患者的临床情况在标准乳果糖治疗剂量中加入利福昔明的限制门槛较低。由于价格高,我们经常参与药企的用药救助计划,为有医疗保险问题的患者促成购药。In the future, we anticipate the introduction of direct-acting inhibitors of ammoniagenesis for the treatment of HE. One such compound, glycerol phenyl butyrate, was recently found to signicantly improve HE in cirrhotic patients. Interestingly, the glycerol phenyl butyrate effect appeared to be additive to rifaximin, suggesting future combination therapies for patients with the most resistant forms of HE.展望了氨生成直接抑制剂治疗肝性脑病的应用前景,甘油苯基丁酸酯是最近发现的化合物的一种,能显著改善肝硬化患者的肝性脑病。有趣的是,甘油苯基丁酸酯和利福昔明有协同作用,这表明对于顽固性脑病将来有可能联合用药。Following discharge, we typically reassess patients on a monthly basis unless they fail to stabilize. Eventually, most patients are followed in 6-month intervals, concomitantly with their biannual screening appointments for hepatocellular cancer. Venous ammonia levels are not routinely followed in clinically stable patients.出院后,我们通常每月重新评估患者病情。之后大多数患者每隔6个月随访一次,每两年进行一次的肝癌筛查,病情稳定的患者不用常规复查血氨水平。Conclusion结论In the past 27 years, the TIPS procedure has evolved to become an important therapeutic option in the management of complications of portal hypertension, namely, variceal bleeding and ascites. This article emphasizes on the important aspects of immediate and long-term post–procedural patient care. The management of patients who are treated for ascites has been addressed separately as the postprocedural management of these patients is usually more complicated.在过去的27年里,TIPS术已经成为门静脉高压食管胃底曲张静脉破裂出血和顽固性腹水的重要治疗选择,本文总结术后即刻治疗和长期随访的重要注意事项,由于腹水患者的术后管理通常更为复杂,因此对腹水患者实行单独管理。References参考文献(略)
From the Society for Clinical Vascular Surgery Factors predicting failure of retrieval of inferior vena cava filters --来自美国临床血管外科学会下腔静脉滤器回收失败的预测因素分析Katherine L. Morrow. MS. James Bena, Ms, Sean P. Lyden. MD, Ezequiel Paradi, MD, and Christopher J. Smolock, MD, Cleveland. OhiofABSTRACT 摘要Objective: Inferior vena cava (IVC) filters have been commonly used to prevent pulmonary embolism in patients with deep vein thrombosis. However, IVC filters have been associated with risks, including IVC perforation, filter migration, fracture, and thrombosis. Filter retrieval has not always been successful. Our objective was to identify the factors associated with failure of retrieval of IVC filters.目的:下腔静脉滤器是预防深静脉血栓患者肺栓塞的常用方法。然而腔静脉滤器置入存在下腔静脉穿孔、滤器移位、滤器折断及滤器内血栓形成等风险。不是所有置入体内的滤器都能成功取出的,本研究的目的是找出与滤器回收失败相关的影响因素。Methods: The present study was an institutional review board-approved retrospective medical record review of patients who had undergone IVC filter retrieval attempts at the Department of Vascular Surgery at Cleveland Clinic from 2011 to 2018. The patients were identified by International Classification of Diseases code query, and data were gathered regarding demographics, filter position, procedure details, and patient outcomes. Computed tomography imaging and venography was used to determine the IVC filter location before retrieval.方法:本研究是一项伦理委员会批准的回顾性研究,通过就诊医疗文书分析了2011年至2018年在克利夫兰诊所血管外科(尝试)进行腔静脉滤器回收的所有患者资料。采用国际疾病分类编码筛选患者,主要搜集滤器形态、位置、操作及患者预后等数据。滤器回收前行CT和静脉造影检查以确定腔静脉滤器的位置。Results: We identified 295 filter retrieval attempts in 294 patients. No procedural IVC ruptures, morbidity, or mortality occurred. Retrieval was successful for 249 filters (84.4%). The median filter dwell time was 196 days for the successful retrievals compared with 375 days for the failed retrieval attempts (P=.004). Penetration of the filter tines through the caval wall occurred in 291 filters (98.6%). However, the hook/apex (HA) of 31 filters (10.5%) had become embedded or had penetrated through the caval wall. The hook/apex and collar (HA+C) of 33 filters (11.2%) were embedded or had penetrated through the caval wall. The failure rate of filter retrieval with the HA embedded was 48.4% (15 of 31). The failure rate with the HA+C embedded was 66.7% (22 of 33). Finally, the failure rate for filters without these issues was 3.9% (9 of 231). The failure rate for HA and HA+C was greater than that for those without these issues (P < .001) but did not differ between the two issues (P =.14). Among those with computed tomography scans, the association of any portion of the filter with other adjacent retroperitoneal structures was not related to an increased rate of retrieval failure (P=.16). Complex retrieval methods involving endobronchial forceps, ballooning, or snaring the collar of the filter was associated with increased retrieval failure compared with simple retrieval involving snaring the hook of the filter (P < .001). The failure rates decreased over time (P=.004). Of the patients with failed retrieval attempts, 8% experienced subsequent venous thromboembolism.结果:共294例患者接受了295次滤器(尝试)取出术,无操作相关的滤器断裂、医源性损伤或患者死亡,249个滤器被成功回收(84.4%)。成功取出的滤器体内停留平均时间为196天,在研究时段内未能取出者平均置入时间为375天(P=0.004)。发现291个滤器(98.6%)的滤齿穿透腔静脉壁,但是只有31个滤器(0.5%)的回收钩/顶端(HA)嵌入或穿透下腔壁。33个滤器(11.29%)的回收钩/顶点和领口部(HA+C)嵌入或穿透管腔壁。回收钩/顶端(HA)嵌入的滤器回收失败率为48.4%(5 / 31)。回收钩/顶端及领口部同时嵌入血管壁(HA+C)的失败率为66.7%(33例中有22例)。最后,没有这些问题的滤器回收失败率是3.9%(9/231)。存在HA和HA+C嵌入的回收失败率比没有这些问题的过滤器的失败率大(P< .001),但HA和HA+C之间没有统计学差异(P=.14)。CT扫描发现滤器的任一部分与其邻近的腹膜后结构的相对位置关系与回收失败率增加无关(P=.16)。与标准的圈套滤器取出钩相比应用活检钳、球囊剥离及圈套器圈套滤器衣领部等方法的应用与高更高的回收失败率正相关 (P < 0.01)。回收失败率随着时间推移会下降(P < 0.04),8%滤器回收失败的患者后续并发了血栓栓塞事件。Conclusions: Retrieval should be attempted for all IVC filters, irrespective of the chronicity and complexity, given the procedural safety. Tine penetration was nearly ubiquitous; however, IVC filters with the HA or HA+C imbedded into or penetrating through the caval wall was a predictor of retrieval failure.结论:不考虑滤器留置的长期性和复杂性的话,所有腔静脉滤器都应该回收。滤器齿穿透血管壁普遍存在,滤器回收钩嵌入(穿透)血管壁(HA)或滤器回收钩和滤器领口部(HA+C)同时嵌入或穿透腔静脉壁是回收失败的预测因子。Keywords: Deep vein thrombosis; Vena cava filter; Hook/apex and collar; Inferior vena cava; Pulmonary embolism【关键词】深静脉血栓形成;腔静脉滤器;回收钩/滤器领口部;下腔静脉;肺栓塞Inferior vena cava (IVC) filters have been commonly used to prevent pulmonary embolism (PE) in patients with deep vein thrombosis (DVT), despite inconclusive evidence regarding the overall effects on morbidity and mortality posed by these devices. Although IVC filters have been shown to decrease the risk of PE in patients with a contraindication to anticoagulation, filters have also been associated with a range of risks, including IVC perforation, filter migration, fracture, and thrombosis. At present, no clinical practice guidelines are available regarding the optimal timeline for filter retrieval. The rates of filter retrieval attempts have varied widely in the reported studies, and when retrieval has been attempted has not always been successful. The retrieval attempt rates appear to have been increasing modestly over time but have remained lower than the ideal. Although filter retrieval failure has been associated with an increased filter dwell time, the effect of the filter position relative to the caval wall and surrounding structures has not been fully elucidated. Thus, the objective of the present study was to identify the factors associated with failure to retrieve IVC filters.下腔静脉(IVC)滤器通常用于预防深静脉血栓(DVT)患者的肺栓塞(PE),虽然关于这些医疗器具对患者发病率和死亡率的总体影响尚无确凿证据。腔静脉滤器已被证明可降低抗凝禁忌患者肺栓塞的风险,但腔静脉滤器也与一系列风险相关,主要包括静脉血管穿透、滤器移位、折断和滤器内血栓形成。目前,还没有临床指南界定最佳滤器回收时机。在已发表的研究中,滤器回收率各不相同,并且滤器不是每个都能成功取出的。随着时间推移尝试取出率会稍有增加,但整体取出率仍不理想。滤器滞留体内时间随着回收失败而显著增加,滤器的位置对腔静脉壁和周围临近组织影响尚未完全明了,本研究旨在阐述滤器回收失败的影响因素。METHODS 方法The present study was a retrospective medical record review of all patients who had undergone IVC filter retrieval attempts at the Department of Vascular Surgery at Cleveland Clinic from July 2011 through June 2018. The institutional review board approved the present study and allowed for a waiver of informed consent owing to the minimal risk posed to the patients. The patients were identified by International Classification of Disease code query, and patient data were gathered from the electronic medical records. The data collected from the patients’ medical records included demographics, medical history, indication for filter placement, filter type, history of filter thrombosis, institution of filter placement (Cleveland Clinic or outside hospital), filter dwell time, American Society of Anesthesiologists class at the retrieval attempt, and retrieval method (eg, snaring the filter hook or more complex methods such as endobronchial forceps or ballooning).回顾性分析2011年7月至2018年6月在克利夫兰诊所血管外科接受下腔静脉滤器取出尝试的所有患者病历。机构审查委员会批准了本研究,并允许放弃知情同意,因这对患者构成的风险极小。通过国际疾病分类码查询对患者进行识别,并从电子病历中采集患者数据。从患者病历中收集的数据包括人口统计、病史、滤器放置的适应症、类型、血栓形成史、放置机构(克利夫兰诊所或院外)、滤器体内停留时间、美国麻醉师学会分类检索取出尝试,以及取回方法(例如,勾住回收钩或更复杂的方法,如支气管内镜活检钳或球囊扩张使之与血管壁剥离)。Computed tomography (CT) and venography were used to determine the IVC filter location before the retrieval attempt. The filter hook/apex (HA) and collar (HA+C) were determined to be intraluminal, within the caval wall, or penetrating through the caval wall (Fig 1).The filter tines were also assessed to determine whether they were intraluminal or whether any of the tines of a given filter had penetrated through the caval wall. Filter association with adjacent structures such as bowel or the spinal column was determined (Fig 2). Additionally, patency of the IVC was categorized as either<50%>50% stenosed,oroccluded. Imaging studies after filter retrieval were reviewed to determine whether any portion of the filter had been left behind in the patient. Simple filter retrieval was defined as snaring the hook of the filter. In contrast, complex retrieval was defined as any combination of the following: snaring the collar of the filter, using a balloon to dislodge the filter, and/or using endobronchial forceps to retrieve the filter (Fig 3).尝试取出滤器之前完善CT和静脉造影检查以确定滤器的位置。回收钩/顶端(HA)和领口部(HA+C)被判断在腔内、管壁内还是已经穿透管壁(图1)。滤器齿也被评估以确定它们是否为腔内或任一尖端是否穿透腔壁。确定滤器与邻近结构(如肠或脊柱)的关系(图2)。此外,下腔静脉通畅可分为<50%狭窄,>50%狭窄或完全梗阻。检查滤器取出后的图像,以确定滤器断裂部分是否遗留在患者体内。简单的滤器回收定义为圈套器圈套住滤器的回收钩进行回收,而复杂滤器回收定义为任何联合使用了圈套器圈套滤器领口部回收、球囊扩张使之与血管壁剥离后回收或使用内镜活检钳回收(图3)。Continuous measures are summarized using the mean ± standard deviation or median and quartiles, according to whether the measures were normally distributed using the Shapiro-Wilk test. Categorical factors are described using frequencies and percentages. Comparisons of the risk factors for retrieval success were evaluated using the Pearson X2 test for categorical factors and the Kruskal-Wallis test or analysis of variance models for non-normally distributed and normally distributed continuous measures, respectively. Odds ratios for retrieval success with 95% confidence intervals are also presented for each risk factor. Given that only one patient had had multiple filters, no correction for correlation of the responses within the patients was used. Statistical analysis was performed using SAS software, version 9.4 (SAS Institute, Cary, NC). A significance level of P < .05 was assumed for all tests.使用标准差或中位数和四分位数描述连续测量值,用Shapiro-Wilk检验测量值是否正态分布,分类变量用频率和百分比来描述。用Pearson-X2检验滤器回收成功的危险因素的分类变量,用Kruskal-Wallis检验非正态分布和正态分布回收成功的危险因素的连续变量。对于每个风险因素,也给出了95%置信区间的回收成功的优势比。考虑到只有一名患者有多个滤器,没有对患者间不同反应进行比较。使用SAS软件9.4版(SAS Institute,Cary,NC)进行统计分析。所有试验的显著性水平均假定为P<.05。ARTICLE HIGHLIGHTSl Type of Research: Single-center, retrospective cohort study l Key Findings: The retrieval failure rate of 295 inferior vena cava filters in 294 patients for filters with the hook/apex penetrating through the caval wall was 48.4% (15 of 31), with hook/apex and collar penetration through the caval wall was 66.7% (22 of 33), and without these issues was 3.9% (9 of 231). l Take Home Message: Inferior vena cava filters with the hook/apex or hook/apex and collar penetrating through the caval wall had increased rates of retrieval failure. Filter tine penetration into adjacent structures did not significantly affect the retrieval failure rates.文章重点介绍研究类型:单中心回顾性队列研究关键发现:294例患者中295个下腔静脉滤器取出钩/尖端穿透下腔静脉壁的回收失败率为48.4%(15/31),回收钩/领口部穿透下腔静脉壁的回收失败率为66.7%(22/33),没有这些问题的是3.9%(231例中的9例)。重要结论:下腔静脉滤器的钩/尖(HA)或钩/尖和衣领部(HA+C)穿过腔静脉壁增加了回收失败率,滤器齿穿透邻近结构对回收失败率没有显著影响。图1. 滤器相对于血管壁的位置。A,滤器取出钩和衣领部进入血管壁,滤器齿穿透腔静脉壁。B,回收钩,领口部和滤齿穿透腔静脉管壁图2。滤器齿穿透腔静脉壁进入邻近结构:A,肝脏;B,肠管;C,主动脉;D,脊柱。图3. 下腔静脉滤器取出技术:A、圈套住滤器回收钩;B、用球囊将滤器从腔壁分离;C、用支气管内镜活检钳取出滤器。RESULTS 结果A total of 295 filter retrieval attempts in 294 patients were identified. The patient demographic data and medical comorbidities are summarized in Tables I and II. Female gender was associated with increased retrieval failure (P=.049); however, race (P=.48) and age (P=.62) were not. The only medical comorbidity we found associated with an increased risk of retrieval failure was hypercoagulability (P=.024). 294例患者共有295次滤器取出尝试。表1和表2总结了患者的人口统计数据和医疗合并疾病数据。女性性别与取出失败率增加有相关性(P=.049);但是种族(P=.48)和年龄(P=.62)与此无关。我们发现的唯一与取出失败风险增加相关的医学合并症是高凝状态(P=.024)。The vast majority of filters were temporary (n=282; 95.6%), with the remainder permanent (Table III). Retrieval was successful for 249 of the filters (84.4%). Retrieval success was greater for the temporary filters (85.5%) than for the permanent filters (61.5%; P=.020). Of the temporary filters, retrieval success was greater for the Celect filters (93.5%) and Eclipse/Denali filters (93.8%) than for the Option filters (78.4%; P=.002). No procedural IVC ruptures, morbidity, or mortality occurred during the retrieval attempts or within the first 30 days after the procedure. Ten of the filters (3.5%) had a history of filter thrombosis; however, this was not associated with increased retrieval failure (P=.70). 绝大多数滤器是临时性的(n=282;95.6%),其余的是永久性的(表III)。249个滤器(84.4%)回收成功。临时滤器的回收成功率(85.5%)高于永久滤器(61.5%;P<0.020)。在临时滤器中,Celect滤器(93.5%)和Eclipse/Denali滤器(93.8%)的回收成功率高于Option滤器(78.4%;P=0.002)。在围术期及手术后的30天内,没有发生操作相关性腔静脉破裂、操作相关病死事件。其中10个滤器(3.5%)有过血栓形成史,然而这与回收失败率增加无关(P=0.70)。Most of the filters had been placed at our institution (n=227; 76.9%), with the remainder placed at an outside hospital (n=68; 23.1%). The indication for filter placement included a contraindication to anticoagulation (n=100; 34%), bridging for surgery (n=76; 26%), bleeding during anticoagulation therapy (n=41; 24%), clot propagation despite anticoagulation therapy (n=12; 4.1%), prophylaxis for DVT thrombectomy or thrombolysis (n=8; 2.7%), prophylaxis after trauma (n=5; 1.7%), free-floating thrombus in the IVC, iliac vein, or femoral vein (n=4; 1.4%), PE with a limited cardiac reserve (n=3; 1.0%), anticoagulation noncompliance (n=2; 0.7%), and placement despite the lack of a clear indication (n=10; 3.4%). The indication for placement could not be obtained for a subset of the patients whose filter had been placed at an outside hospital (n=34; 12%). 大部分滤器在我们中心放置的(n=227;76.9%),其余的在外部医院放置的(n=68;23.1%)。滤器放置的适应症包括抗凝禁忌症(n= 100;34%)、等待手术(n=76;26%)、抗凝治疗期间出血(n=4 41;24%)、抗凝治疗后血栓仍进展(n =12;4.1%),预防血栓清除或导管溶栓后复发(n=8;2.7%),创伤后预防血栓(n=5;1.7%),腔静脉漂浮血栓、髂静脉或股静脉(n=4;1.4%),肺栓塞并且心功能差(n=3;1%),抗凝不依从(n=2;0.7%);无明确适应症(n=10;3.4%)。滤器于院外放置且无法获得放置指征的(n=34;12%)。表1. 滤器回收成功的人口统计学预测因素The median filter dwell time was 196 days for the filters successfully retrieved and 375 days for the filters with failed retrieval attempts (P=.004; Fig 4). The median dwell time for the permanent filters was 3605 days compared with 196 days for the temporary filters (P < .001). Filters with both hook and collar penetrating through the caval wall had had statistically significantly longer dwell times than filters with the intraluminal hook and collar and filters with only the hook penetrating through the caval wall (P < .001). Filters with an intraluminal hook and collar through the caval wall had an average dwell time of 231 days. Filters with the hook through the caval wall had an average dwell time of 287 days. Filters with both the hook and the collar through the caval wall had an average dwell time of 591 days. 对于成功取出的滤器,中位滤器体内停留时间为196天,对于取出尝试失败的滤器,中位滤器体内停留时间为375天(p=.004; Fig 4)。永久滤器的中位体内停留时间为3605天,而临时滤器的中位体内停留时间为196天(P<.001)。滤器取出钩和衣领部穿透管腔壁的体内停留时间明显长于回收钩和衣领部仅进入腔静脉壁的滤器和仅回收钩穿透管腔壁的滤器(P<.001)。回收钩和衣领部进入管腔壁的滤器平均体内停留时间为231天,回收钩穿透管腔壁的滤器平均体内停留时间为287天,回收钩和衣领部同时穿透管腔壁的滤器平均体内停留时间为591天。表II.滤器回收成功的病史预测因素Penetration of the filter tines through the caval wall occurred in 291 of the filters (98.6%; Table IV). The HA of 31 filters (10.5%) were embedded or penetrating through the caval wall, and the HA+C of 33 (11.2%) were embedded or had penetrated through the caval wall. The failure rate for the retrieval of filters with the HA embedded was 48.4% (15 of 31), that with the HA+C embedded was 66.7% (22 of 33), and that for filters without these issues was 3.9% (9 of 231). The failure rate of both filters with the HA embedded and those with the HA+C embedded was greater than that of those without these issues (P < .001). However, the failure rates between the two did not differ from one another (P=.14; Fig 5). We found a total of six filters in the present study that had fractured and had left ≥1 tine behind after retrieval. Of these six filters, three had been permanent and three temporary. Neither the size of the retrieval sheath (P=.45) nor the use of the coaxial sheaths (P=.65) for filter removal was associated with increased retrieval failure. 291个滤器(98.6%;表IV)的滤齿穿过腔壁。31个滤过器(10.5%)的HA嵌入或穿透腔壁,33个(11.2%)的HA+C嵌入或穿透腔壁。HA嵌入管腔壁回收失败率为48.4%(15/31),HA+C嵌入失败率为66.7%(22/33),无以上问题者为3.9%(9/231)。HA和HA+C嵌入的滤器的回收失败率均高于无此问题者(P<0.001)。然而,两者之间(HA VS HA+C)的回收失败率并没有差异(P=.14;图5)。在本研究中,我们一共发现了6个滤器断裂,在滤器取出后至少有1个残余结构遗留体内。在这6个滤器中,3个是永久性的,3个是临时性的。回收鞘的大小(p=.45)和是否使用同轴系统(P=. 65)和回收失败率增加无关。表III. 回收成功的滤器相关预测因素CT scans of the abdomen before filter retrieval was available for 157 patients (47%). Of these patients, filter tines or hooks were associated with the following structures: bowel (n=50; 32%), spine (n=17; 11%), aorta (n=11; 7%), psoas major muscle (n=6; 3.8%), renal vein (n=5; 3.2%), liver (n=4; 2.5%), heart (n=3; 1.9%), lung (n=2; 1.3%), and pulmonary artery (n=1; 0.6%). Among those with CT scans available, the association of any portion of the filter with other adjacent structures was not related to an increased rate of failed retrieval (P=.16; Table IV). However, six patients had had ≥1 filter tine left behind after retrieval because of filter fracture that had occurred before retrieval. Complex retrieval methods involving endobronchial forceps, ballooning, or snaring the collar of the filter was associated with increased failure rates compared with simple retrieval involving snaring the hook of the filter (P < .001). 157例患者(47%)在滤器取出前进行了腹部CT扫描。在这些患者中,滤齿或回收钩与以下结构相关:肠(n=50;32%)、脊柱(n=17;11%)、主动脉(n=11;7%)、腰大肌(n=6;3.8%)、肾静脉(n=5;3.2%)、肝(n=4;2.5%)、心脏(n=3;1.9%)、肺(n=2;1.3%)和肺动脉(n=1;0.6%)。在那些有CT扫描的患者中,滤器的任何部分与其他邻近结构的关联性与取出失败率的增加无关(P=.16;表IV)。然而,6个病人体内残留至少1个断裂的滤器齿,因为取出前就发现滤器断裂。与简单的圈套滤器回收钩相比,复杂的取回方法包括支气管内镜活检钳,球囊扩张使之与血管壁剥离,或圈套滤器的领口部,这些方法的使用与回收失败率增加正相关(P<.001)。图4. 尝试回收前滤器体内停留时间Before filter retrieval, most patients had had a relatively patent IVC. IVC stenosis of<50% 274="" was="" present="" in="" patients="" ivc="" stenosis="" of="">50% was present in 19 patients (6%), and IVC occlusion was seen in 1 patient (0.3%). Stenosis of >50% or complete occlusion was associated with increased failure of retrieval compared with stenosis of<50% (P=.013; Table IV). 在滤器取出之前,大多数患者有一个相对通畅的下腔静脉。274例(93%)下腔静脉狭窄<50%,19例(6%)下腔静脉狭窄>50%,1例(0.3%)下腔静脉闭塞。大于50%的狭窄或完全闭塞与小于50%的狭窄相比,滤器回收失败率增加(P=.013;表IV)。表IV:第一次尝试取出成功的预测因素The retrieval failure rates had decreased over time (P=.004), suggesting a learning curve was involved with the retrieval process (Fig 6). Of the patients with failed retrieval attempts, 8% had experienced subsequent venous thromboembolism within the first 2 years after the retrieval attempt. Of these patients, two had experienced PE, but that was unrelated to the filter retrieval attempt or the continued presence of the original DVT. Of the 46 filters that were not successfully retrieved, a second retrieval was later attempted for eight (17%), six of which were successful. Any second attempts at filter retrieval were not included within our data analyses in the present study. One patient within our cohort had required open surgical removal of the IVC filter. This patient’s filter had formed a fistula into the duodenum, resulting in anorexia and postprandial pain that necessitated filter retrieval.随着时间的推移回收失败率下降了(P<.004),表明学习曲线与回收过程有关(图6)。在尝试回收失败的患者中,8%的患者在尝试取出后的前2年内发生过静脉血栓栓塞时间。在这些病人中,有两个有肺栓塞,但这与滤器取出尝试或原深静脉血栓的持续存在无关。在未成功取出的46个滤器中,有8个(17%)稍后尝试再次取出,其中6个已成功。在本研究中,我们的数据分析中没有包含任何第二次滤器取出尝试。在我们的队列中有一个病人要求开放手术取出滤器,这个病人的滤器已经形成了一个到十二指肠的瘘,导致厌食和餐后疼痛,需要开放手术将其取出。DISCUSSION 讨论IVC filters have long been a method of preventing PE in patients with a contraindication to anticoagulation or other factors that confer a high risk of venous thromboembolism. In general, filters have been considered a relatively safe device compared with the potentially devastating morbidity and mortality associated with PE. However, filters are not without risk, especially because of the tendency to leave filters in place long past the point at which they should have been retrieved. A systematic review of 37 studies and 6834 retrievable IVC filters demonstrated an average filter retrieval rate of merely 37%, with most filter-related complications occurring >30 days after placement.对于抗凝或其他导致静脉血栓栓塞高风险的因素有禁忌症的患者,腔静脉滤器长期以来一直是一种预防肺栓塞的方法。一般来说,与潜在的可致毁灭性发病率和死亡率的肺栓塞相比,腔静脉滤器是相对安全的医疗器具。然而滤器并非完全没有风险,特别是本该取出的滤器。对37项研究和6834个可回收腔静脉滤器的系统回顾表明,平均滤器回收率仅为37%,大多数滤器相关并发症发生在放置后30天以后。图5. 按滤器位置分层的回收失败率。HA,钩/顶点;HA+C,钩/顶点和滤器衣领部The overall effectiveness of IVC filters in reducing morbidity and mortality has continued to be debated. Filters have been demonstrated to reduce the risk of PE but have also been associated with an increased risk of proximal DVT.2,11,12Studies of filter effectiveness are lacking, partially owing to the question of equipoise in conducting such studies. However, current evidence has suggested that the overall morbidity and mortality might not be significantly affected by the use of IVC filters. 滤器在降低发病率和死亡率方面的总体效果仍有争议。滤器已被证明可以降低肺栓塞的风险,但也与髂股静脉血栓增加的风险有关。滤器有效性的研究仍缺乏,部分由于在这样的研究中的均衡问题。然而,目前的证据表明,使用腔静脉滤器可能不会对总的发病率和死亡率产生显著影响。No significant complications or patient morbidity were associated with any of the 295 filter retrieval attempts in the present study, suggesting that this procedure is safe and should be attempted for any patient with an IVC filter that is no longer needed. Although the risks associated with a long filter dwell time are low, the risks in attempting retrieval appear to be minimal. Thus, it would be prudent to attempt retrieval for all patients once the filter is no longer needed. Although permanent filters are designed to be left within the patient indefinitely, 13 retrievals were attempted for permanent filters within our cohort. The decision to remove these filters was at the discretion of the surgeon and retrieval had generally been attempted because the patient no longer had any indication for the filter to remain in place. Complex filter retrieval techniques included snaring the collar of the filter instead of the hook, using endobronchial forceps to grasp the filter, and ballooning the filter away from the caval wall. These techniques were often used during the more difficult filter retrieval attempts, once simple retrieval by snaring the hook of the filter had failed. 在本研究中295例滤器取出尝试中,没有与操作相关的并发症,表明该操作是安全的,所以对于任何不再需要滤器的患者都应该尝试取出。虽然滤器长时间体内停留的风险很低,但尝试取出的风险似乎很小。因此,当不再需要滤器时,尝试回收所有患者体内滤器是谨慎推荐的。尽管永久性滤过器被设计为无限期地留在患者体内,但在我们的队列中尝试了13次永久性滤器的取出。当没有继续将滤器留置在患者体内的适应症时都应尝试取出,取出这些滤器的决定是由外科医生决定的。复杂的滤器回收技术包括圈套滤器领口部,用支气管内镜活检钳取滤过器,球囊扩张使之与血管壁剥离。这些技术通常在常规回收操作失败后的更困难的滤器回收尝试中使用。图6. 按年份分层的滤器回收失败率Tine penetration through the caval wall was nearly ubiquitous within our patient cohort and, thus, could not be used as a predictor of filter retrieval failure. However, the position of the hook/apex and collar relative to the caval wall can be very useful in predicting whether filter retrieval will be successful. Association of the filter hook/apex itself or the filter hook/apex and collar with the caval wall has been significantly associated statistically with an increased rate of retrieval failure and, thus, can be used as a predictive factor when assessing the likelihood of procedural success. Association of any aspect of the filter with nearby structures, including the bowel, liver, and spine, was not associated with an increased rate of retrieval failure. 滤器齿穿透腔静脉壁的情况在我们的患者队列中很常见,因此,不能作为滤器回收失败的预测因素。然而,回收钩/尖端和领口部相对于管壁的位置对于预测滤器回收是否成功非常有用。回收钩/顶端本身(HA)或回收钩/顶点和领口部(HA+C)与腔静脉壁的相关性在统计学上与回收失败率的增加显著相关,因此,在评估手术成功的可能性时,可作为预测因素。滤器的任何部分与邻近结构(包括肠、肝和脊柱)的关联与回收失败率的增加无关。A total of 10 patients (3.4%) in the present study had had a filter placed despite the lack of a clear indication for placement, such as a contraindication to anticoagulation therapy. Filter placement outside the recommended indications has also been demonstrated in other studies.13Although this trend accounted for only a small portion of our patient cohort, it is still concerning, because filters should not be placed without a clear indication. Care should be taken when assessing patients for the possibility of filter placement, and filters should only be placed when the potential benefits outweigh the possible risks. 本研究共有10名患者(3.4%)在没有明确的放置指征(如抗凝治疗禁忌症)的情况下放置了滤器。在推荐适应症之外的滤器放置也在其他研究中也有报道。尽管这一趋势只占我们患者队列的一小部分,但它仍然令人关注,因为没有明确的适应症就不应放置滤器。在评估患者放置过滤器的可能性时应小心,只有当潜在的益处大于可能的风险时才应放置滤器。In recent years, placement of IVC filters has appeared to be decreasing modestly, although the rate of IVC filter retrieval attempts has been increasing yet has remained low. Imperative to the goal of decreasing IVC filter complications is the need for improved rates of retrieval, because most complications have occurred in filters that have remained indwelling longer than would be ideal. The retrieval rates might be improved through implementation of a multidisciplinary protocol, which has previously been demonstrated at another institution.近年来,尽管腔静脉滤器的取出尝试率一直在增加,但滤器的放置似乎在适度减少。降低滤器并发症的目标必须提高取回率,因为大多数并发症发生在滤器留置的时间比理想的要长。通过实施一个多学科会诊方案,回收率可能会有所提高,这一点以前已经在另一个机构得到证实。Our study was limited by the inherent nature of retrospective reviews. Some data were limited for collection, especially because a subset of patients had had their filter placed at an outside institution. The approach to the evaluation and technique was developed throughout the study period. Additionally, we performed a single-institution study, potentially limiting the ability to generalize the results to the population at large. We also had a low number of permanent filters compared with those designed to be temporary to study the differences between these groups. Additionally, our institution likely treats a skewed number of patients with malpositioned filters and long filter dwell times. We also did not include filter tilt in our analysis, although previous studies have suggested that filter tilt might have a significant effect on filter retrieval success. Future directions could include implementation of a filter retrieval protocol to ensure that the device will be removed as soon as it is no longer medically indicated. Such a protocol would be a relatively simple method to decrease the complications associated with IVC filters and has been supported by the results of the present study, which indicated that retrieval should be attempted for all filters, given the demonstrated procedural safety.我们的研究受到回顾性研究固有性质的限制。一些数据的收集受到限制,特别是因为有一部分患者在外院放置的腔静脉滤器。评估方法和技术是在整个研究期间发展起来的。此外,我们做的是一项单中心研究,这可能会限制将结果推广到广大人群的能力。另外,和临时滤器数量相比我们永久性滤器数量偏少,不足以研究亚组之间的差异。此外,我们的机构回收了可致研究数据偏倚数量的移位滤器和超回收窗滤器。我们也没有在我们的分析中包括滤器倾斜,尽管先前的研究表明滤器倾斜可能对滤器回收成功有重大影响。未来的方向可能包括实现滤器回收流程,以确保临床不再需要时被移除。这样一个方案将是一个相对简单的方法,以减少与滤器相关的并发症,并已得到本研究结果的支持,即考虑到已被证明的操作安全性,应尝试对所有滤器进行回收。CONCLUSIONS结论The results of the present study have suggested that retrieval should be attempted for all IVC filters, irrespective of the chronicity and complexity, given the procedural safety. In our study, tine penetration was nearly ubiquitous. However, IVC filters with the HA or HAtC imbedded into or penetrating through the caval wall are predictors of retrieval failure. Obtaining a preoperative CT scan can be helpful in assessing the difficulty or complexity of retrieval. Improved rates of filter retrieval should be attempted to decrease the risks associated with prolonged filter dwell times. We encourage the use of IVC filter retrieval protocols as a relatively simple method to limit the filter dwell times.本研究的结果表明,无论程序的长期性和复杂性如何,都应尝试对所有滤器进行回收,因为操作安全。在我们的研究中,滤器齿穿透血管壁几乎无处不在。然而,回收钩(HA)或回收钩和滤器领口部(HA+C)嵌入或穿透腔壁是回收失败的预测因素。术前CT扫描有助于评估回收的难度或复杂性。应尝试提高滤器回收率,以减少与延长滤器体内停留时间相关的风险。我们鼓励使用滤器回收多学科会诊流程作为一种相对简单的方法来减少滤器体内停留时间。AUTHOR CONTRIBUTIONS 作者贡献(略)Conception and design: KM, JB, SL, EP, CS Analysis and interpretation: KM, JB, CS Data collection: KM Writing the article: KM Critical revision of the article: KM, JB, SL, EP, CS Final approval of the article: KM, JB, SL, EP, CS Statistical analysis: JB Obtained funding: Not applicable Overall responsibility: KMREFERENCES参考文献(略)