杜英杰,王古巖,楊麗靜,石 佳,吉冰洋,鄭 哲
·臨床研究·
不同劑量氨甲環(huán)酸對心臟瓣膜術(shù)患者血液的保護(hù)作用
杜英杰,王古巖,楊麗靜,石 佳,吉冰洋,鄭 哲
目的比較低、中、高三種不同劑量氨甲環(huán)酸對心臟瓣膜手術(shù)患者的血液保護(hù)效果。方法2009年2月至2010年2月,擇期行心臟瓣膜手術(shù)患者150例,隨機(jī)分成3組:低劑量組(n=49),負(fù)荷量10 mg/kg,維持量2 mg/(kg·h);中劑量組(n=51),負(fù)荷劑量為15 mg/kg,維持量為8 mg/(kg·h);高劑量組(n=50),負(fù)荷劑量為30 mg/kg,維持量為16 mg/(kg·h)。記錄術(shù)后胸管引流量,紅細(xì)胞、血漿、血小板的使用情況,以及住院死亡和并發(fā)癥發(fā)生率。結(jié)果低、中、高三組患者術(shù)后6 h引流量[(324.90±196.05)vs.(303.73±185.03)vs.(255.31±121.81)ml]、24 h引流量[(611.67±281.56)vs.(601.50±304.33)vs.(555.82± 239.16)ml]和總引流量[(744.48±350.90)vs.(712.20±359.15)vs.(658.67±290.07)ml]比較差異均無統(tǒng)計(jì)學(xué)意義(P>0.05)。三種劑量下,異體紅細(xì)胞、新鮮冰凍血漿、血小板的使用率及使用量亦無統(tǒng)計(jì)學(xué)差異(P>0.05)。三組患者并發(fā)癥發(fā)生率無統(tǒng)計(jì)學(xué)意義(P>0.05)。結(jié)論低、中、高三種劑量的氨甲環(huán)酸對瓣膜手術(shù)患者術(shù)后出血、輸血及術(shù)后并發(fā)癥的影響無顯著差異,術(shù)中推薦應(yīng)用低劑量。
氨甲環(huán)酸;心臟瓣膜手術(shù);血液保護(hù);術(shù)后出血;輸血
體外循環(huán)(cardiopulmanary bypass,CPB)心臟手術(shù)中血液與異體管道接觸引起纖溶激活,血漿中凝血因子及血小板過度消耗,導(dǎo)致圍術(shù)期大量出血,異體血液制品使用風(fēng)險(xiǎn)增加[1-2]。這不僅增加傳染?。ㄈ绺窝缀桶滩〉龋┑母腥緳C(jī)率,還增加了再次手術(shù)風(fēng)險(xiǎn),增加術(shù)后發(fā)病率和死亡率[1-2]。
自氨甲環(huán)酸應(yīng)用于臨床以來,能夠達(dá)到血液保護(hù)作用的使用劑量仍在爭論之中[3-7]。目前,臨床使用劑量方案相差懸殊,總量范圍從1~20 g不等[8]。因此,有必要尋找更低而確保有效的使用劑量。我們注意到Nuttall等人建議使用較低的劑量,同時(shí)可確保血漿濃度維持在20 mg/L。具體劑量為負(fù)荷劑量10 mg/kg之后以2 mg/(kg·h)速度持續(xù)至手術(shù)結(jié)束[9]。本研究根據(jù)藥代動力學(xué)研究結(jié)果采用前瞻性、隨機(jī)、雙盲臨床試驗(yàn)將常用高劑量減半[10],通過設(shè)計(jì)低、中、高三種給藥劑量,比較不同劑量氨甲環(huán)酸對于心臟瓣膜手術(shù)術(shù)后出血和輸血的影響,以確定氨甲環(huán)酸在心臟瓣膜手術(shù)中應(yīng)用的最佳劑量。
1.1 臨床資料 本研究經(jīng)本院醫(yī)學(xué)倫理委員會批準(zhǔn),患者均簽署知情同意書。2009年2月至2010年2月,擇期行心臟瓣膜手術(shù)的患者150例,年齡20~74歲,體重指數(shù)16~32 kg/m2,ASA分級I~Ⅲ級,NYHA分級I~Ⅲ級,左室射血分?jǐn)?shù)>35%,既往無心臟手術(shù)史和/或急性心肌梗死(>1個(gè)月)病史;術(shù)前無貧血[血紅蛋白(Hb)>100 g/L],未服用抗血小板藥物(如阿司匹林、波立維等),凝血、肝、腎功能未見異常。采用隨機(jī)數(shù)字表法,將患者隨機(jī)分為3組:低劑量組(L組,n=49)、中劑量組(M組,n=51)和高劑量組(H組,n=50)。三組藥液均由一名麻醉人員在手術(shù)前按照隨機(jī)號的組別配制,該人員不參與患者的治療。參與手術(shù)的醫(yī)護(hù)人員均不知道患者的分組情況。
1.2 麻醉方法 術(shù)前1.5 h口服地西泮10 mg,麻醉前30 min肌肉注射嗎啡10 mg。入室后建立靜脈通路,常規(guī)監(jiān)測ECG、脈搏氧飽和度(SpO2)、有創(chuàng)動脈壓、鼻咽溫和直腸溫。麻醉誘導(dǎo):靜脈注射咪達(dá)唑侖0.1 mg/kg、芬太尼5~10 μg/kg和哌庫溴銨0.1 mg/kg,氣管插管后行機(jī)械通氣,維持呼氣末二氧化碳分壓(PETCO2)35~45 mm Hg(1 mm Hg=0.133 kPa)。頸內(nèi)靜脈穿刺監(jiān)測CVP。不同組別氨甲環(huán)酸(批號:20090035,上海信宜醫(yī)藥公司)的使用情況:L組負(fù)荷量為10 mg/kg,維持量為2 mg/(kg·h);M組的負(fù)荷劑量是15 mg/kg,維持量為8 mg/(kg·h);H組的負(fù)荷劑量為30 mg/kg,維持量為16 mg/(kg ·h)。三組負(fù)荷量均在麻醉誘導(dǎo)后輸注,30 min內(nèi)輸完,然后給予維持量持續(xù)輸注直至手術(shù)結(jié)束。麻醉維持:吸入1%~2%七氟醚,間斷靜脈注射芬太尼和哌庫溴銨,持續(xù)泵入丙泊酚。
1.3 手術(shù)方法 手術(shù)采用標(biāo)準(zhǔn)胸骨正中切口,靜脈注射肝素400 U/kg,5 min后測定ACT值(HEMOCHRON?Jr.signature多功能醫(yī)用凝血自動測定儀,ACT+,美國),ACT在CPB開始和期間維持480 s以上。在心臟停跳下行瓣膜置換或瓣膜成形手術(shù)。脫離體外循環(huán)機(jī)后,魚精蛋白中和肝素的比例為0.8~1∶1,測定中和后的ACT值,使ACT<150 s。常規(guī)留置胸腔、心包、縱隔引流管接無菌水封瓶,止血關(guān)胸。術(shù)中采用BW-8100A型自體血液回收機(jī)行自體血回輸。
1.4 指標(biāo)測定 術(shù)后24 h抽取患者中心靜脈血測定:Hb、血小板(Plt)、血肌酐及尿素氮。記錄術(shù)后6 h、24 h及術(shù)后總的胸管引流量。記錄術(shù)中、術(shù)后使用異體紅細(xì)胞(RBC)、Plt及新鮮冰凍血漿(FFP)的使用率及輸入量。輸入RBC的指證為Hb<90 g/L;輸入FFP的指證為術(shù)后胸管引流量>150 ml/h或>100 ml/h連續(xù)2 h。記錄手術(shù)時(shí)間、CPB時(shí)間、主動脈阻斷時(shí)間,記錄自體血液回收機(jī)的使用情況。記錄術(shù)后ICU停留時(shí)間、住院時(shí)間,以及住院期間死亡和并發(fā)癥的發(fā)生情況。
1.5 統(tǒng)計(jì)方法 應(yīng)用SPSS 17.0統(tǒng)計(jì)軟件對數(shù)據(jù)進(jìn)行分析。計(jì)量資料采用均數(shù)±標(biāo)準(zhǔn)差(±s)表示,非正態(tài)分布資料經(jīng)對數(shù)轉(zhuǎn)化成近似正態(tài)分布資料后進(jìn)行檢驗(yàn)。三組之間組間比較應(yīng)用單因素方差分析,組內(nèi)比較采用重復(fù)測量設(shè)計(jì)的方差分析。計(jì)數(shù)資料組間比較應(yīng)用卡方檢驗(yàn),等級資料進(jìn)行秩和檢驗(yàn),P<0.05為差異有統(tǒng)計(jì)學(xué)意義。
三組患者術(shù)前性別、年齡、心、腎功能及其他合并癥等一般情況、術(shù)中的手術(shù)時(shí)間、CPB時(shí)間、阻斷時(shí)間及術(shù)中使用自體血液回收情況的指標(biāo)比較差異無統(tǒng)計(jì)學(xué)意義(P>0.05)。術(shù)后Hb、血肌酐、尿素氮的值比較差異亦無統(tǒng)計(jì)學(xué)意義(P>0.05)。患者均無院內(nèi)死亡,其他術(shù)后并發(fā)癥的發(fā)生情況詳見表1。L組、M組、H組術(shù)后6 h、24 h、術(shù)后總引流量、血液制品(RBC,F(xiàn)FP,Plt)的使用率組間比較差異均無統(tǒng)計(jì)學(xué)意義(P>0.05),詳見表2。
表1 術(shù)前、術(shù)中及術(shù)后資料(±s)
表1 術(shù)前、術(shù)中及術(shù)后資料(±s)
注:LVEF:左室射血分?jǐn)?shù);LVEDV:左室舒張末期容積;PT:凝血酶原時(shí)間;INR:國際標(biāo)準(zhǔn)化比值;NS:比較無意義。
指標(biāo)/分組L組(n=49)M組(n=51)H組(n=50)P值年齡(歲)53.12±9.8749.96±13.8550.18±11.930.347男性2923210.190體重指數(shù)(kg/m2)23.93±3.2123.11±2.9223.58±3.700.462心功能分級2.16±0.512.35±0.592.12±0.480.075術(shù)前LVEF(%)61.00±6.7161.14±8.2659.28±9.510.457 LVDEV(mm)53.55±8.3353.73±11.1156.76±9.810.190心胸比0.57±0.070.58±0.090.60±0.070.261術(shù)前Hb(g/L)142.18±17.93139.61±24.47139.24±17.490.734術(shù)前血清肌酐(μmol/L)79.38±16.8385.67±63.575.38±39.980.053術(shù)前尿素氮(mmol/L)2.46±0.872.39±0.912.21±0.820.351術(shù)前PT(S)14.18±1.7414.24±1.0214.05±1.020.762凝血酶原活動度(%)85.22±18.6984.69±13.6789.38±14.210.263 INR1.12±0.171.14±0.141.11±0.110.562手術(shù)時(shí)間(min)219.80±59.99219.65±48.79221.06±68.520.972 CPB時(shí)間(min)103.18±42.4097.35±35.95106.1±54.740.870阻斷時(shí)間(min)72.02±30.7668.73±27.7579.18±44.690.678血液回收例數(shù)(使用率)13(26.53%)12(23.53%)12(24%)0.993回輸血量(ml)350.86±225.66263.44±146.02431.82±329.420.895插管時(shí)間(h)14.95±9.7015.02±11.1814.74±8.020.989 ICU時(shí)間(d)2.08±1.342.78±1.962.28±1.910.878住院天數(shù)(d)10.61±5.4411.24±8.149.64±4.820.511術(shù)后1 d WBC(×109/L)12.11±3.5412.03±3.5911.88±3.760.953術(shù)后1 d Plt(×109/L)117.56±39.78114.90±34.97115.92±34.220.935術(shù)后1d Hb(g/L)109.23±9.94109.12±13.47108.02±13.130.864出院Hb(g/L)110.51±22.07112.54±14.41110.06±14.600.761術(shù)后尿素氮(mmol/L)3.42±2.243.20±1.763.64±1.370.480術(shù)后血肌酐(μmol/L)96.50±57.87105.27±113.62101.07±33.110.849新發(fā)室早(例)1220.786新發(fā)房顫(例)2020.396二次開胸(例)1111.000床旁血濾(例)0111.000二次插管(例)0101.000氣管切開(例)0101.000意識障礙(例)1010.548死亡(例)000NS急性心梗(例)000NS傷口、縱膈感染(例)000NS
表2 手術(shù)出血、輸血情況(±s)
表2 手術(shù)出血、輸血情況(±s)
指標(biāo)L組(n=49)M組(n=51)H組(n=50)P值引流液6 h(ml)324.90±196.05303.73±185.03255.31±121.810.369引流液24 h(ml)611.67±281.56601.50±304.33555.82±239.160.676總引流液(ml)744.48±350.90712.20±359.15658.67±290.070.504 RBC量(u,使用率)1.84±12.14(48.98%)2.24±2.51(54.90%)2.70±5.25(52.00%)0.500/0.881 FFP量(ml,使用率)155.10±311.62(20.29%)168.00±394.58(18.84%)240.00±474.66(26.09%)0.523/0.528 Plt量(u,使用率)0.02±0.14/(2.04%)0.02±0.14(2.00%)0.08±0.34(6.00%)0.324/0.444
研究表明纖溶激活是術(shù)后不可避免的大量出血的主要原因,合理使用有效抗纖溶藥物可降低這些風(fēng)險(xiǎn)。自2007年9月抗纖溶藥物血液保護(hù)作用的臨床試驗(yàn)(BART)研究指出抑肽酶可增加術(shù)后死亡率后抑肽酶退出市場[10],之后抗纖溶藥物的關(guān)注點(diǎn)集中在氨甲環(huán)酸上。氨甲環(huán)酸為人工合成的賴氨酸類似物,其作用機(jī)理主要是競爭性占據(jù)纖溶酶(原)上的賴氨酸結(jié)合點(diǎn),阻斷纖溶酶原與纖維蛋白上的賴氨酸結(jié)合,使纖溶酶無法形成,即便形成纖溶酶,因不能與纖維蛋白結(jié)合,也能夠限制對纖維蛋白的水解作用,使纖維蛋白降解產(chǎn)物生成減少,從而起到抗纖維蛋白溶解的作用[11]。多項(xiàng)研究均顯示,氨甲環(huán)酸用于心臟手術(shù)可減少術(shù)后出血和輸血,且與抑肽酶相比術(shù)后死亡率明顯降低[10],故現(xiàn)已常規(guī)應(yīng)用于CPB心臟手術(shù)。最近的指南推薦CPB心臟手術(shù)使用氨甲環(huán)酸的級別為Class I,Level A[12-13]。國內(nèi)及國外大規(guī)模隨機(jī)臨床試驗(yàn)[10,14]、2007年發(fā)表于《Circulation》[6]、2011年Cochrane的薈萃分析及最新系統(tǒng)綜述均顯示[15-16],氨甲環(huán)酸用于心臟手術(shù)可以減少術(shù)后出血和輸血量,具有血液保護(hù)作用。
在所有的劑量方案之中,BART研究的劑量最為常用,負(fù)荷劑量為30 mg/kg繼之以16 mg/(kg·h)維持至手術(shù)結(jié)束[10]。但是研究提示使用BART實(shí)驗(yàn)中推薦劑量,直到術(shù)后6 h氨甲環(huán)酸的平均濃度持續(xù)高于所推薦的可達(dá)到抑制組織纖溶酶原激活的濃度需求[17]。在以前的藥物動力學(xué)研究中,Dowd等人發(fā)現(xiàn)這個(gè)劑量可使體內(nèi)氨甲環(huán)酸的濃度達(dá)到800 μM(約120 mg/L),遠(yuǎn)高于實(shí)際需求[3]。因?yàn)槭聦?shí)上,CPB期間有效抑制纖溶的目標(biāo)濃度是10~20 mg/L[18]。類似的,近來Fox團(tuán)隊(duì)建議使用氨甲環(huán)酸的劑量是達(dá)到血漿濃度>20 mg/L[19]。同時(shí),多項(xiàng)研究指出使用高劑量的氨甲環(huán)酸術(shù)后癲癇的發(fā)生明顯增加(劑量為61到259 mg/kg)[20-26]。臨床應(yīng)用氨甲環(huán)酸時(shí)需警惕劑量相關(guān)的興奮性中毒問題。由于氨甲環(huán)酸是非特異性纖溶酶的抑制劑,且可與抑制神經(jīng)遞質(zhì)γ-氨基丁酸(GABA)的A型受體結(jié)合,阻滯GABA的中樞神經(jīng)系統(tǒng)抑制作用。因此,大劑量使用時(shí)可導(dǎo)致興奮性中毒[27]。
本結(jié)果表明在術(shù)中輸血、術(shù)后輸血、術(shù)后出血及主要并發(fā)癥方面給予三種劑量的氨甲環(huán)酸作用效果沒有差別,故提示較低劑量的氨甲環(huán)酸即可滿足心臟瓣膜手術(shù)患者的血液保護(hù)要求。同時(shí),2012年最新關(guān)于氨甲環(huán)酸劑量的研究與本研究結(jié)論大體一致[8]。因此,聯(lián)合考慮安全性、有效性及花費(fèi)效益等多種因素,推薦術(shù)中使用低劑量的氨甲環(huán)酸。在臨床應(yīng)用中需要更加嚴(yán)格的控制圍術(shù)期氨甲環(huán)酸的使用劑量,清晰認(rèn)識患者并發(fā)癥與手術(shù)操作對該藥術(shù)后副作用的影響。由于本研究排除了術(shù)前合并肝、腎功能障礙的高?;颊撸奔篆h(huán)酸能否安全有效地應(yīng)用于此類患者和劑量問題,有待進(jìn)一步研究。
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Comparison of blood-saving effects of different dose of tranexamic acid in cardiac valvular surgery
Du Ying-jie,Wang Gu-yan,Yang Li-jing,Shi Jia,Ji Bing-yang,Zheng Zhe
Department of Anesthesiology,F(xiàn)uwai Hospital,State Key Laboratory of Cardiovascular Disease,National Center for cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100037,China
Wang Gu-yan,Email:guyanwang2006@163.com
ObjectiveTo compare the blood-saving effect of different dose of tranexamic acid in cardiac valvular surgery.MethodsFrom February 2009 to February 2010,one hundred and fifty patients were randomly divided into 3 groups according to different dose of tranexamic acid in cardiac valvular surgery:low dose group(n=49),the loading dose was 10 mg/kg and maintenance dose was 2 mg/(kg·h);moderate dose group(n=51),the loading dose was 15 mg/kg and maintenance dose was 8 mg/(kg·h);high dose group(n=50),the loading dose was 30 mg/kg and maintenance dose was 16 mg/(kg·h).The bolus of tranexamic acid was infused intravenously within 30 min after induction followed by continuous infusion until the end of operation.The volume of chest tube drainage was recorded at 6 h and 24 h after operation.The total volume was calculated.The requirement for transfusion of allogeneic red blood cells(RBC),platelet(Plt)and fresh frozen plasma(FFP)were also recorded.ResultsThere were no significant differences in the volume of chest tube drainage at 6 h((324.90±196.05)vs.(303.73±185.03)vs.(255.31±121.81)ml),24 h((611.67±281.56)vs.(601.50±304.33)vs.(555.82±239.16)ml)and the total volume((744.48±350.90)vs.(712.20±359.15)vs.(658.67±290.07)ml)after operation(P>0.05).Moreover,the requirements for transfusion of allogeneic RBC,Plt and FFP were not significantly different(P>0.05).No fatalities occurred during the hospital stay in any of the 3 groups.ConclusionThere are no significant differences in transfusion and chest tube drainage in the 3 different dose groups.Therefore,low dose of tranexamic acid is recommended for blood-saving in cardiac valvular surgery.
Tranexamic acid;Cardiac valve surgery;Blood-saving effect;Postoperative hemorrhage;Blood transfusion
R654.1
A
1672-1403(2013)04-0004-05
2012-11-12)
2013-01-07)
中央級公益性科研院所基本科研業(yè)務(wù)費(fèi)資助(2009-F06)
10037北京,北京協(xié)和醫(yī)學(xué)院,中國醫(yī)學(xué)科學(xué)院,國家心血管病中心,心血管疾病國家重點(diǎn)實(shí)驗(yàn)室,阜外心血管病醫(yī)院,麻醉科(杜英杰,王古巖,楊麗靜,石 佳),體外循環(huán)科(吉冰洋),心外科(鄭 哲)
王古巖,Email:guyanwang2006@163.com