石建平，趙夢(mèng)華(綜述)，徐寶元(審校)

(邯鄲市中心醫(yī)院心內(nèi)科，河北 邯鄲 056001)

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癌癥患者導(dǎo)管相關(guān)血栓形成的防治

石建平，趙夢(mèng)華(綜述)，徐寶元(審校)

(邯鄲市中心醫(yī)院心內(nèi)科，河北 邯鄲 056001)

摘要：臨床治療癌癥患者時(shí)為了給予化療藥物、血液制品和胃腸道外營(yíng)養(yǎng)，常給患者置入中心靜脈導(dǎo)管，而血栓形成是置入導(dǎo)管后的常見并發(fā)癥。導(dǎo)管相關(guān)血栓形成(CRT)可導(dǎo)致肺栓塞、感染以及導(dǎo)管故障。大部分CRT并無癥狀，因此需要臨床醫(yī)師對(duì)此并發(fā)癥提高警覺。CRT的診斷依賴于多普勒超聲或靜脈造影檢查，一旦確診，需權(quán)衡抗凝治療風(fēng)險(xiǎn)與CRT并發(fā)癥風(fēng)險(xiǎn)后再行決定治療策略。

關(guān)鍵詞：癌癥；靜脈血栓形成；中心靜脈導(dǎo)管；抗凝治療

越來越多的癌癥患者由于需要給予化療藥物、血液制品和胃腸道外營(yíng)養(yǎng)，而被置入中心靜脈導(dǎo)管[1]。靜脈血栓栓塞癥(venous thromboembolism，VTE)是癌癥患者的常見并發(fā)癥，雖然癌癥患者中的大部分VTE為下肢深靜脈血栓形成，但也不乏導(dǎo)管相關(guān)靜脈血栓形成(catheter related thrombosis，CRT)。研究表明，CRT的總體發(fā)生率為14%~18%，癥狀性CRT發(fā)生率約為5%[2]。CRT的并發(fā)癥包括肺栓塞、感染和導(dǎo)管故障?，F(xiàn)對(duì)癌癥患者發(fā)生CRT的危險(xiǎn)因素、CRT的診斷、預(yù)防和治療策略予以綜述。

1CRT的危險(xiǎn)因素

1.1置入操作相關(guān)危險(xiǎn)因素置入操作時(shí)對(duì)血管壁的損傷可造成血管內(nèi)皮細(xì)胞功能紊亂，從而導(dǎo)致血栓形成。不同血管入路置入導(dǎo)管時(shí)對(duì)血管內(nèi)皮損傷的程度并不相同，因此血管入路部位也是發(fā)生CRT的重要決定因素。研究表明，從左側(cè)血管置入的中心靜脈導(dǎo)管(central venous catheter，CVC)發(fā)生CRT的風(fēng)險(xiǎn)高于右側(cè)CVC，而從股靜脈置入的CVC比從鎖骨下靜脈和頸靜脈置入的CVC有更高的血栓形成風(fēng)險(xiǎn)[3]。此外，多次置入操作以及既往CVC置入也會(huì)增加CRT發(fā)生的風(fēng)險(xiǎn)[4]。

1.2導(dǎo)管相關(guān)危險(xiǎn)因素CVC的化學(xué)組成對(duì)血栓形成亦有影響，聚乙烯導(dǎo)管比新的多聚體(如聚烏拉坦)有更高的致血栓性；同樣，導(dǎo)管的硬度也十分重要，硬導(dǎo)管特別是臨時(shí)性CVC更易損傷血管壁，而柔軟性導(dǎo)管則具有更好的順應(yīng)性[5]。導(dǎo)管頭端的位置也顯著影響CRT的發(fā)生率，導(dǎo)管頭端如位于上腔靜脈較高的位置時(shí)易發(fā)生血栓形成[6]。有一前瞻性觀察性研究表明，經(jīng)外周血管置入的CVC有較高的導(dǎo)管頭端位置異常發(fā)生率[7]；其CRT發(fā)生率為2%~7%[8]。經(jīng)頭靜脈置入導(dǎo)管的血栓形成發(fā)生率最高(7%)，而經(jīng)貴要靜脈和肱靜脈置入導(dǎo)管的血栓形成發(fā)生率分別為5%和2%[9]。

1.3患者相關(guān)危險(xiǎn)因素患者相關(guān)危險(xiǎn)因素包括既往VTE史[3]、遺傳性血栓形成傾向[10]、感染[11]以及惡性腫瘤的類型[12]。遺傳性血栓形成傾向與CRT的相關(guān)性目前尚存在較大的爭(zhēng)議[5]，而更多的學(xué)者現(xiàn)已接受急性感染是VTE的獨(dú)立危險(xiǎn)因素[13]。實(shí)體器官腫瘤特別是卵巢癌，比淋巴瘤、骨髓瘤和白血病有更高發(fā)生CRT的風(fēng)險(xiǎn)[4]。

2診斷

大部分CRT并無癥狀，因而其診斷具有一定的挑戰(zhàn)性。CRT的癥狀包括上肢、頸部或面部腫脹疼痛，上肢、頸部或胸壁的紅斑、頭痛以及上肢靜脈曲張等[14]。無癥狀血栓形成可在行CT或探查導(dǎo)管是否通暢時(shí)被發(fā)現(xiàn)。對(duì)無癥狀CRT的初始影像學(xué)檢查應(yīng)首選雙功超聲檢查[15]。雙功超聲對(duì)累及頸、腋、鎖骨下遠(yuǎn)端和上肢靜脈血栓形成的診斷靈敏度為97%，特異度為96%[16]。由于解剖學(xué)的關(guān)系，雙功超聲對(duì)診斷上腔靜脈、鎖骨下近端和頭臂靜脈血栓形成則較為困難。CRT的金標(biāo)準(zhǔn)診斷檢查方法為靜脈造影[14]，考慮到對(duì)比劑毒性和放射暴露的風(fēng)險(xiǎn)，所以此種檢查應(yīng)保留給臨床高度懷疑但雙功超聲檢查為陰性結(jié)果的患者。而增強(qiáng)CT則對(duì)深部中央靜脈和肺動(dòng)脈血管床的血栓栓塞具有準(zhǔn)確診斷的優(yōu)勢(shì)[5]。不同于D-二聚體對(duì)下肢深靜脈血栓形成和肺栓塞的提示診斷作用，D-二聚體對(duì)臨床懷疑CRT患者的診斷價(jià)值尚不明確；此外，由于癌癥患者具有較高的D-二聚體假陽性發(fā)生率，故也限制了此項(xiàng)檢查在該患者群中的應(yīng)用[17]。

3并發(fā)癥

CRT最嚴(yán)重的并發(fā)癥是肺栓塞，有癥狀肺栓塞的發(fā)生率為5%~14%，而無癥狀肺栓塞的發(fā)生率為15%~36%[5]。CRT最常見的并發(fā)癥為感染。CRT的長(zhǎng)期并發(fā)癥為血栓形成后綜合征，其發(fā)生率可高達(dá)35%[18]。血栓形成后綜合征的臨床表現(xiàn)包括肢體疼痛、沉重感、腫脹、痙攣、水腫、靜脈曲張以及潰瘍。

4預(yù)防

4.1沖洗為維持導(dǎo)管的通暢性，需在每次操作后沖洗導(dǎo)管，而未行操作則至少每周需沖洗導(dǎo)管1次[5]。雖然許多臨床醫(yī)師推薦使用肝素進(jìn)行沖洗，但支持此種方法的證據(jù)較少見。事實(shí)上使用肝素(10 U/mL)沖洗維持CVC通暢性的效果并不優(yōu)于生理鹽水沖洗[19]。此外，使用肝素沖洗尚存在可能引起肝素誘導(dǎo)的血小板減少的風(fēng)險(xiǎn)。

4.2維生素K拮抗劑早年對(duì)置入CVC的癌癥患者給予小劑量華法林(1 mg/d)以預(yù)防CRT的方法曾經(jīng)非常流行，但隨后的隨機(jī)安慰劑對(duì)照研究并未能證明此方法的有效性[20]。迄今為止，最大的試驗(yàn)WARP研究將置入CVC的癌癥患者分為未服用華法林組、小劑量華法林組和調(diào)整劑量華法林組(國(guó)際標(biāo)準(zhǔn)化比率：1.5~2.0)以觀察華法林預(yù)防CRT的效果；結(jié)果表明，未服用華法林組和小劑量華法林組的CRT發(fā)生率無差別；雖然調(diào)整劑量華法林組可降低CRT發(fā)生率，但卻明顯增加主要出血的發(fā)生率[21]。因此，當(dāng)今的指南不再推薦使用華法林預(yù)防CRT[22-23]。

4.3普通肝素有一隨機(jī)試驗(yàn)將置入CVC的癌癥患者分為接受連續(xù)性靜脈輸注預(yù)防性劑量普通肝素組[100 IU/(kg·d)]和生理鹽水組(500 mL/d)，結(jié)果表明，普通肝素組CRT的發(fā)生率為1.5%，生理鹽水組為12.6%(P=0.03)[24]。但此種方法每日需靜脈輸注的不方便性限制了其臨床應(yīng)用。

4.4低分子肝素對(duì)低分子肝素預(yù)防CRT隨機(jī)對(duì)照試驗(yàn)進(jìn)行匯總分析的結(jié)果表明，低分子肝素并不能有效地降低有癥狀CRT的發(fā)生率(RR=0.54，95%CI0.28~1.05)，但對(duì)主要出血風(fēng)險(xiǎn)亦無明顯影響(RR=0.68，95%CI0.10~4.78)[5]。最近的指南指出，雖然低分子肝素用于預(yù)防癌癥患者CRT時(shí)不增加主要出血風(fēng)險(xiǎn)，但也并無明確獲益[22-23]。

5治療

當(dāng)導(dǎo)管發(fā)生阻塞即便并無癥狀提示為CRT所致時(shí)，也應(yīng)將稀釋后的5000 U尿激酶注入導(dǎo)管腔并保留2 h[25]。如導(dǎo)管仍然阻塞則應(yīng)行胸部X線檢查以證實(shí)導(dǎo)管的位置并除外發(fā)生阻塞的機(jī)械性原因，然后再注入5000 U尿激酶并保留12~24 h[5]。由于治療性劑量纖溶藥物可增加主要出血風(fēng)險(xiǎn)并缺乏長(zhǎng)期獲益的證據(jù)，所以對(duì)可疑或確診的CRT不推薦給予治療性劑量纖溶藥物[15]。有一小型非隨機(jī)前瞻性研究對(duì)74例經(jīng)放射學(xué)檢查確診的CRT實(shí)體腫瘤患者給予了3個(gè)月抗凝治療，結(jié)果表明，32例(43%)患者移除了CVC，3例(4%)發(fā)生了再發(fā)CRT，7例(9%)發(fā)生了主要出血事件[26]。雖然對(duì)癌癥患者CRT給予抗凝治療的證據(jù)較為有限，但大部分學(xué)者認(rèn)為應(yīng)至少給予3個(gè)月的抗凝治療[23]。對(duì)正在接受化療和抗生素治療的癌癥患者很難保證華法林抗凝治療的安全性，另外基于低分子肝素治療癌癥患者VTE無可爭(zhēng)議的獲益證據(jù)，所以對(duì)癌癥患者CRT的抗凝治療推薦給予低分子肝素[27]。由于僅對(duì)少數(shù)VTE患者給予新型口服抗凝藥物治療，對(duì)CRT患者尚無應(yīng)用此類藥物的報(bào)道，所以目前尚不能對(duì)新型口服抗凝藥物用于治療癌癥患者CRT做出評(píng)論[2,28]。血小板減少癥是CRT患者給予抗凝治療時(shí)需考慮的一個(gè)重要問題，特別是對(duì)正在接受骨髓抑制劑治療的患者則更為重要，指南推薦血小板計(jì)數(shù)>80×109/L時(shí)可給予全劑量抗凝治療[29]。而在臨床實(shí)踐中，更多的臨床醫(yī)師對(duì)血小板計(jì)數(shù)>50×109/L的患者給予全劑量抗凝治療；對(duì)血小板計(jì)數(shù)為30×109/L~50×109/L的患者給予小劑量抗凝治療；對(duì)血小板計(jì)數(shù)<30×109/L的患者則不給予抗凝治療[30]。如果仍然需要CVC，導(dǎo)管的功能和位置亦正常，同時(shí)無導(dǎo)管相關(guān)感染的跡象時(shí)，當(dāng)今的指南不推薦移除CVC[22-23]。但如果不符合上述任一標(biāo)準(zhǔn)時(shí)則應(yīng)移除CVC。移除導(dǎo)管的最佳時(shí)間目前尚無明確的結(jié)論，臨床通常是在給予抗凝治療后的3~5 d移除導(dǎo)管[2]。

6小結(jié)

大部分癌癥患者的CRT并無癥狀，因此為了及時(shí)診斷和治療需要應(yīng)對(duì)此并發(fā)癥給予高度的警覺。CRT的危險(xiǎn)因素包括置入操作因素、導(dǎo)管相關(guān)因素和患者相關(guān)危險(xiǎn)因素。雖然CRT的診斷金標(biāo)準(zhǔn)為靜脈造影，但多數(shù)患者行靜脈超聲和CT檢查即可得到明確診斷。一旦確診為CRT，至少需給予低分子肝素抗凝治療3個(gè)月。如果需要保留CVC，而CVC仍通暢且無感染的證據(jù)時(shí)，應(yīng)避免移除導(dǎo)管。對(duì)懷疑為CRT的癌癥患者可不行D-二聚體檢查。對(duì)需要置入CVC的癌癥患者可不行遺傳性血栓形成傾向篩查及常規(guī)給予血栓預(yù)防措施。

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Study on the Prevention and Treatment of Catheter-Related Thrombosis in Cancer PatientsSHIJian-ping,ZHAOMeng-hua,XUBao-yuan.(DepartmentofCardiology，HandanCentralHospital，Handan056001，China)

Abstract:Central venous catheters are commonly used for the administration of chemotherapy,blood products and parenteral nutrition in patients with haematological malignancy.Thrombosis is a recognized complication of the placement of such devices especially in oncology patients.Catheter-related thrombi(CRT) may lead to pulmonary embolism and infection,as well as catheter failure and potential delays in treatment.The vast majority of CRT are asymptomatic,thus a high index of suspicion is required in making the diagnosis.Doppler ultrasound or venography may be employed to identify CRT.Once confirmed,the initiation of treatment needs to balance between the risk of anticoagulation and potential complications of CRT.

Key words：Cancer； Venous thrombosis； Central venous catheter； Anticoagulation

收稿日期：2014-07-08修回日期：2014-10-31編輯：鄭雪

doi：10.3969/j.issn.1006-2084.2015.09.025

中圖分類號(hào):R473.73

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：1006-2084(2015)09-1602-03