特利加压素联合生长抑素治疗肝硬化并发上消化道出血患者疗效研究

作者单位:271219山东省泰安市新汶矿业集团有限责任公司中心医院消化内科(刘慧);检验科(郁磊);山东第一医科大学第二附属医院消化内科(张诒凤)
第一作者:刘慧,女,37岁,大学本科,主治医师㊂E -mail:lclj456@
㊃肝硬化㊃
特利加压素联合生长抑素治疗肝硬化并发上消化道出血患者疗效研究
刘慧,张诒凤,郁磊
㊀㊀ʌ摘要ɔ㊀目的㊀研究应用特利加压素联合生长抑素治疗肝硬化并发上消化道出血患者的疗效及其血清胰高血糖素
(GCG)和一氧化氮(NO)水平的变化㊂方法㊀2018年5月~2019年7月我院消化内科收治的104例乙型肝炎肝硬化并发
上消化道出血患者,被随机分为对照组52例和观察组52例,分别给予生长抑素或生长抑素联合特利加压素治疗,两组均
治疗3d㊂采用免疫散射比浊法检测血清高敏C 反应蛋白(hs -CRP),采用化学发光法检测血清皮质醇(COR),采用化学发光免疫分析法检测血清GCG 和采用间接比色法检测血清NO 水平㊂结果㊀观察组呕血停止㊁血压平稳和止血时间分别为(5.2ʃ2.1)h㊁(11.9ʃ3.1)h 和(21.9ʃ7.1)h,显著短于对照组ʌ分别为(8.5ʃ2.3)h㊁(15.5ʃ5.3)h 和(30.5ʃ5.3)h,P <
0.05ɔ,观察组出血控制率为94.2%,显著高于对照组的78.9%(P <0.05)㊂观察组死亡3例(5.8%),对照组死亡11例(21.2%,P <0.05);治疗后,观察组外周血血红蛋白水平为(107.3ʃ19.4)g /L,显著高于对照组ʌ(98.6ʃ17.9)g /L,P <
0.05ɔ,血细胞比容为(37.6ʃ5.8)%,显著高于对照组ʌ(29.4ʃ6.5)%,P <0.05ɔ,血小板计数为(101.4ʃ19.2)ˑ109/L,显著高于对照组ʌ(92.8ʃ18.4)ˑ109/L,P <0.05ɔ;观察组门静脉血流为(481.3ʃ91.7)mL /min,显著慢于对照组ʌ(608.6ʃ
98.5)mL /min,P <0.05ɔ,脾静脉血流为(231.4ʃ44.2)mL /min,显著低于对照组ʌ(302.8ʃ52.4)mL /min,P <0.05ɔ,门静脉内径为(12.6ʃ1.1)mm,显著低于对照组ʌ(14.7ʃ1.0)mm,P <0.05ɔ,脾静脉内径为(9.2ʃ0.8)mm,低于对照组ʌ(12.6ʃ0.9)mm,P <0.05ɔ;血清hs -CRP 水平为(6.5ʃ1.1)μg /L,显著低于对照组ʌ(12.3ʃ3.2)μg /L,P <0.05ɔ,血清COR 水平为
(281.2ʃ12.6)μg /L,显著低于对照组ʌ(318.7ʃ14.9)g /L,P <0.05ɔ,血清GCG 水平为(149.8ʃ17.4)ng /L,显著低于对照组ʌ(182.4ʃ19.3)ng /L,P <0.05ɔ,而血清NO 水平为(119.4ʃ10.7)μmol /L,显著高于对照组ʌ(96.9ʃ12.6)μmol /L,P <0.05ɔ㊂结论㊀特利加压素联合生长抑素治疗肝硬化并发上消化道出血患者止血效果好,可能与稳定了血液循环功能,降
低了血清应激指标有关㊂
㊀㊀ʌ关键词ɔ㊀肝硬化;上消化道出血;特利加压素;生长抑素;胰高血糖素;一氧化氮;治疗㊀㊀DOI:10.3969/j.issn.1672-5069.2020.06.025
㊀㊀Application of terlipressin and somatostatincombination in treatment of cirrhotic patients with upper gastrointestinal
bleeding㊀Liu Hui ,Zhang Yifeng ,Yu Lei .Department of Gastroenterology ,Central Hospital ,Xinwen Mining Group Co.,Ltd.,
Tai an 271219,Shandong Province ,China
㊀㊀ʌAbstract ɔ㊀Objective ㊀The purpose of this study was to investigate the efficacy of terlipressin and somatostatin
combination in the treatment of cirrhotic patients with upper gastrointestinal bleeding,and serum glucagon (GCG)and nitric oxide
(NO)level changes.Methods ㊀104hepatitis B cirrhotic patients with upper gastrointestinal bleeding were enrolled in our hospital
and were randomly divided into observation (n =52)and control group (n =52).The patients in the control group were treated with somatostatin,and those in the observation group were treated with terlipressin based on somatostatin.The regimen lasted for3days.
Serum high -sensitivity C -reactive protein (hs -CRP),cortisol (COR),glucagon (GCG)and nitric oxide (NO)were assayed.Results ㊀The stopping time of hematemesis,stable blood pressure and hemostatic time in the combination group were (5.2ʃ2.1)
h,(11.9ʃ3.1)h and (21.9ʃ7.1)h,significantly shorter than ʌ(8.5ʃ2.3)h,(15.5ʃ5.3)h and (30.5ʃ5.3)h,respectively,P <0.05ɔin the control,and the the effective rate in the former was 94.2%,much higher than 78.9%(P <0.05)in the latter;after treatment,the blood hemoglobin was (107.3ʃ19.4)g /L,much higher than [(98.6ʃ17.9)g /L,P <0.05],the hematocrit
was (37.6ʃ5.8)%,much higher thanʌ(29.4ʃ6.5)%,P <0.
05ɔand platelet counts was (101.4ʃ19.2)ˑ109/L,significantly higher than ʌ(92.8ʃ18.4)ˑ109/L,P <0.05ɔin the control;the portal vein blood flow was (481.3ʃ91.7)mL /
min,much slower than [(608.6ʃ98.5)mL /min,P <0.05],
the splenic vein blood flow was (231.4ʃ44.2)mL /min,much
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slower than[(302.8ʃ52.4)mL/min,P<0.05],the diameter of portal vein was(12.6ʃ1.1)mm,significantly lower thanʌ(14. 7ʃ1.0)mm,P<0.05ɔand the splenic vein diameter was(9.2ʃ0.8)mm,much lower thanʌ(12.6ʃ0.9)mm,P<0.05ɔin the control;serum hs-CRP level was(6.5ʃ1.1)μg/L,much lower thanʌ(12.3ʃ3.2)μg/L,P<0.05ɔ,serum COR level was (281.2ʃ12.6)μg/L,much lower thanʌ(318.7ʃ14.9)g/L,P<0.05ɔand serum GCG level was(149.8ʃ17.4)ng/L,much lower thanʌ(182.4ʃ19.3)ng/L,P<0.05ɔ,while serum NO level was(119.4ʃ10.7)μmol/L,significantly higher thanʌ(96.9ʃ12.6)μmol/L,P<0.05ɔin the control.Conclusion㊀The successful hemostasis is obtained by administration of terlipressin and somatostatin combination in cirrhotic patients with variceal hemorrhage,which might reduce blood GCG and elevate NO levels.㊀㊀ʌKey wordsɔ㊀Liver cirrhosis;Variceal hemorrhage;Terlipressin;Somatostatin;Glucagon;Nitric oxide;Therapy
㊀㊀上消化道出血为肝硬化临床常见的并发症之一,起病急㊁发展快㊁出血量大,发病原因为门静脉压力升高㊂出血可造成出血性休克,严重威胁患者生命[1]㊂药物治疗为肝硬化并发上消化道出血的主要临床治疗方案,生长抑素为人工合成的活性十四氨基酸肽,可通过抑制胃分泌胃酸和收缩内脏血管起到止血作用,为上消化道出血治疗的一线用药,疗效确切,但仍无法完全解除患者门静脉高压[2]㊂特利加压素为人工合成的加压素类似物,临床研究[3]发现,特利加压素可特异性收缩动脉㊁静脉和内脏小静脉,控制上消化道活动性出血,从而达到止血的目的㊂胰高血糖素(glucagon,GCG)和一氧化氮(nitric oxide,NO)均为影响血液流变学的因素㊂本研究应用特利加压素联合生长抑素治疗肝硬化并发上消化道出血患者,观察了疗效及血清GCG和NO水平的变化,现报道如下㊂
1㊀资料与方法
1.1一般资料㊀2018年5月~2019年7月我院消化内科收治的乙型肝炎肝硬化并发上消化道出血患者104例,男62例,女42例;年龄37~74岁,平均年龄为(57.6ʃ5.1)岁;肝功能Child分级A级4例,B级60例,C级40例;病程2~11年,平均(5.2ʃ1.91)年㊂符合‘肝硬化门静脉高压食管胃静脉曲张出血防治指南“[4]的诊断标准㊂排除标准:①入组前1月内使用过止血药物或行内镜下止血者;②合并自身免疫性疾病㊁营养不良等导致免疫系统功能不全者;
③既往有肝脏手术史[5];④合并消化性溃疡㊁穿孔等可能导致消化道出血疾者⑤合并恶性肿瘤㊁血液系统疾病㊂采用随机数字表法将患者分成观察组52例和对照组52例,两组性别㊁年龄㊁肝功能Child分级和病程等一般资料比较无统计学差异(P>0.05),具有可比性㊂本研究方案已经获得我院医学伦理委员会审核批准,患者签署知情同意书㊂
1.2治疗方法㊀给予两组患者护肝㊁补液和预防感染等常规治疗,嘱患者禁食水㊂在对照组,给予生长抑素(扬子江药业集团有限公司,国药准字
H20066708)250μg静脉注射后,再以25μg㊃h-1持续静脉泵入;在观察组,在对照组治疗的基础上给予特利加压素(深圳翰宇药业股份有限公司,国药准字H20093804)2mg静脉注射,再以1mg静脉注射, 1次/4h㊂两组均持续治疗3d㊂
1.3检测指标㊀使用全自动生化分析仪(BS-380型,深圳迈瑞生物医疗电子股份有限公司)及其配套试剂测定血生化指标;采用免疫散射比浊法检测血清高敏C反应蛋白(high-sensitivity C-reactive protein,hs-CRP)水平(深圳市锦瑞生物科技有限公司);采用化学发光法检测血清皮质醇(cortisol, COR)水平(厦门市波生生物技术有限公司);采用化学发光免疫分析法检测血清GCG水平;采用间接比色法检测血清NO水平(福建福缘生物科技有限公司);使用Apsaras US-8型彩色多普勒超声系统检测门静脉血流㊁脾静脉血流㊁门静脉内径和脾静脉内径㊂
1.4疗效判定㊀根据‘肝硬化门静脉高压食管胃静脉曲张出血防治指南“[4]将疗效分为显效:用药72h 内呕血㊁黑便等症状消失,生命体征恢复平稳,胃液中无血迹;有效:用药72h内呕血和便血明显好转,生命体征较平稳,胃液中无血迹或略带血迹;无效:用药72h后出血仍未控制,生命体征不稳定,胃液中有红色液体㊂
1.5统计学方法㊀应用SPSS21.0软件处理和分析,计量资料以(xʃs)表示,采用t检验,率的比较采用x2检验㊂P<0.05表示差异具有统计学意义㊂
2㊀结果
2.1两组疗效比较㊀观察组止血指标和出血控制率显著优于或高于对照组,差异具有统计学意义(P< 0.05,表1㊁表2);观察组死亡3例(5.8%),对照组死亡11例(21.2%,P<0.05)㊂
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表1㊀两组止血指标(xʃs)比较
例数呕血停止(h)血压平稳(h)止血时间(h)住院时间(d)观察组49 5.2ʃ2.1①11.9ʃ3.1①21.9ʃ7.1①7.5ʃ2.4①
对照组418.5ʃ2.315.5ʃ5.330.5ʃ5.310.6ʃ3.1
㊀㊀与对照组比,①P<0.05
2.2两组血常规指标变化的比较㊀治疗后,观察组外周血血红蛋白㊁血细胞比容和血小板计数显著高于对照组(P<0.05,表3)㊂
2.3两组门静脉指标比较㊀在止血后经超声检查,发现观察组门静脉血流和脾静脉血流均显著慢于对照组,门静脉内径和脾静脉内径均显著小于对照组,差异具有统计学意义(P<0.05,表4)㊂
2.4两组血清应激指标比较㊀治疗后,观察组血清应激指标均显著低于对照组,差异具有统计学意义(P< 0.05,表5)㊂
表2㊀两组疗效[n(%)]比较
例数显效有效无效止血
观察组5221(40.4)28(53.8)3(5.77)49(94.2)①对照组5214(26.9)27(51.9)11(21.2)41(78.9)㊀㊀与对照组比,①P<0.05
表3㊀两组血液指标(xʃs)比较
例数血红蛋白(g/L)血细胞比容(%)血小板(ˑ109/L)观察组治疗前5289.4ʃ11.621.7ʃ4.267.2ʃ16.0治疗后49107.3ʃ19.4①37.6ʃ5.8①101.4ʃ19.2①对照组治疗前5290.2ʃ11.922.5ʃ4.565.9ʃ16.3治疗后4198.6ʃ17.929.4ʃ6.592.8ʃ18.4
㊀㊀与对照组比,①P<0.05
表4㊀两组门静脉指标(xʃs)比较
例数门静脉血流(mL/min)门静脉内径(mm)脾静脉血流(mL/min)脾静脉内径(mm)观察组49481.3ʃ91.7①12.6ʃ1.1①231.4ʃ44.2①9.2ʃ0.8①对照组41608.6ʃ98.514.7ʃ1.0302.8ʃ52.411.6ʃ0.9
㊀㊀与对照组比,①P<0.05
表5㊀两组血清应激指标(xʃs)比较
例数hs-CRP(μg/L)COR(μg/L)GCG(ng/L)NO(μmol/L)观察组治疗前5217.3ʃ4.8358.5ʃ17.4221.2ʃ24.8124.1ʃ18.5治疗后49 6.5ʃ1.1①281.2ʃ12.6①149.8ʃ17.4①119.4ʃ10.7①对照组治疗前5217.1ʃ5.1361.2ʃ21.7220.6ʃ21.9123.5ʃ16.4治疗后4112.3ʃ3.2318.7ʃ14.9182.4ʃ19.396.9ʃ12.6
㊀㊀与对照组比,①P<0.05
3㊀讨论
肝硬化门静脉高压症可导致食管胃底静脉曲张破裂出血[7]㊂虽然研究[8,9]显示消化内镜下止血快速有效,但对医院设备和医师技术要求均较高㊂流行病学研究[10]发现,我国肝硬化患者并发上消化道出血多为轻中度出血,药物治疗也可取得较好的治疗效果㊂生长抑素可减少胃酸和胃泌素的分泌,避免高酸性的胃液侵蚀出血部位的溃疡面,同时控制多种血管活性物质的分泌,控制内脏血流[11]㊂特利加压素为高效血管收缩剂,可特异性收缩内脏血管平滑肌,强效降低血流量,从而控制消化道出血[12]㊂既往研究[13]显示,肝硬化并发上消化道出血发生时,可导致肝脏合成hs-CRP,并激活人体应激反应,使得COR分泌增加㊂肝硬化患者肝组织内NO 表达减少,外周血NO水平上升,而NO具有扩张血管㊁提高血流量的作用,可促进肝硬化上消化出血病
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情进展[14]㊂研究[15]显示肝硬化患者GCG分泌增加,不仅可增强肝脏的糖异生作用,还可扩张内脏血管及增加门静脉血流量,并增加侧支循环进入食管胃底静脉,增加出血风险㊂生长抑素可升高胃内pH 值,极大减轻出血部位酸腐蚀作用,抑制机体炎症反应及应激作用,同时直接抑制胰腺分泌GCG,降低内脏血流[16]㊂特利加压素被水解后可产生持续性低水平的赖氨加压素,可减少内脏血供,减轻上消化道血管破裂处血管压力,抑制出血,避免持续出血刺激hs-CRP和COR释放,抑制机体炎症免疫反应,改善机体微循环㊂目前,特利加压素对NO和GCG的作用机制尚未明确,但研究[17]显示肝硬化患者血清NO水平上升主要由L-精氨酸经诱导型一氧化氮合酶作用生成,而L-精氨酸经诱导型一氧化氮合酶可受到多种炎性因子作用,促进NO表达,而GCG释放增加可受出血损伤刺激和应激性高代谢环境影响,推测特利加压素可通过抑制机体炎症和应激反应,控制GCG分泌㊂
门静脉高压为肝硬化的最常见的表现,也是上消化道出血的主要原因㊂因此,控制门静脉高压也是治疗肝硬化并发上消化道出血的重点[18,19]㊂生长抑素能提高胃内pH值,有利于血小板聚集及抑制胃蛋白酶原的激活,促进胃内止血,而特利加压素在此基础上通过减少侧支循环血流量㊁控制肝脏血流量,降低肝静脉压力梯度,止血速度和效果均优于对照组㊂因此观察组患者治疗后止血时间缩短,病死率降低㊂
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(收稿:2020-03-20)
(本文编辑:陈从新)
㊃068㊃实用肝脏病杂志2020年11月第23卷第6期㊀J Prac Hepatol,November.2020.Vol.23No.6。