普萘洛尔对肝硬化门静脉高压患者血流动力学的影响和疗效观察
|
摘要
目的评估短期口服普萘洛尔对肝硬化食管胃底静脉曲张患者是否产生血流动力学应答反应,并进一步探讨其应答状态对预防食管胃静脉曲张破裂出血(EGVB)的临床意义。方法收集自2015年3月-2016年10月南京大学医学院附属鼓楼医院消化科的42例肝硬化食管胃底静脉曲张患者的临床资料。在口服普萘洛尔前和服药7 d后分别测定肝静脉压力梯度(HVPG),并对完成2次HVPG测定的患者进行随访,随访终点为发生食管胃底静脉曲张破裂出血事件。HVPG值下降20%以上或绝对值降至12 mm Hg以下被定义血流动力学应答反应。本研究通过配对样本t检验及χ~2检验方法比较服药前后HVPG值改变及应答者和无应答者EGVB的发生率,并通过回归分析探讨EGVB的独立危险因素。结果最终纳入分析的患者共32例,其总体应答率为43. 75%(应答/无应答:14例/18例),总体HVPG值从(18. 3±5. 0) mm Hg下降至(15. 0±4. 9) mm Hg(t=4. 640,P <0. 001)。应答者和无应答者间的年龄、性别、病因、肝功能分级基础HVPG值均无明显差异(P值均> 0. 05),应答者的第2次HVPG值明显低于无应答者[(11. 5±3. 5) mm Hg vs (17. 7±5. 0) mm Hg,t=5. 470,P <0. 001]。基于3年随访后,共8例患者出现EGVB;应答者EGVB发生率明显低于无应答者(χ~2=8. 529,P=0. 004)。多因素Cox回归分析显示既往出血史(风险比=12. 917,95%可信区间:1. 861～89. 648,P=0. 010)和第2次HVPG值(风险比=1. 481,95%可信区间:1. 102～1. 990,P=0. 009)均是EGVB的独立危险因素。结论肝硬化食管胃底静脉曲张患者短期口服普萘洛尔后的血流动力学应答率是43. 75%。应答者发生EGVB的风险明显低于无应答者。既往发生过出血或第2次HVPG较高者发生出血的风险明显升高。
Objective To investigate whether short-term oral administration of propranolol can induce hemodynamic response in patients with liver cirrhosis and esophageal and gastric varices,as well as the clinical significance of such response in the prevention of esophagogastric variceal bleeding( EGVB). Methods A total of 42 cirrhotic patients with esophageal and gastric varices who were treated in Department of Gastroenterology in Affiliated Drum Tower Hospital of Nanjing University Medical School from March 2015 to October 2016 were enrolled. Hepatic venous pressure gradient( HVPG) was measured before and after 7 days of oral administration of propranolol. The patients who completed these two HVPG measurements were followed up until the development of EGVB. Hemodynamic response was defined as a reduction in HVPG by at least 20% or an absolute value of HVPG of ≤12 mm Hg. The paired samples t-test and the chi-square test were used to compare the change in HVPG after propranolol administration and the incidence of EGVB between responders and non-responders.A regression analysis was used to identify the independent risk factors for EGVB. Results A total of 32 patients were included in the final analysis,with an overall response rate of 43. 75%( 14 responders and 18 non-responders),and the overall HVPG value decreased from18. 3 ± 5. 0 mm Hg to 15. 0 ± 4. 9 mm Hg( t = 4. 640,P < 0. 001). There were no significant differences in age,sex,etiology,liver function,and baseline HVPG between the responders and the non-responders( all P > 0. 05),and the responders had a significantly higher HVPG value at the second time of measurement than the non-responders( 11. 5 ± 3. 5 mm Hg vs 17. 7 ± 5. 0 mm Hg,t = 5. 470,P <0. 001). During the 3-year follow-up,8 patients developed EGVB,and the responders had a significantly lower incidence rate of EGVB than the non-responders( χ2= 8. 529,P = 0. 004). The multivariate Cox regression analysis showed that a past history of bleeding( hazard ratio [HR]= 12. 917,95% confidence interval [CI]: 1. 861-89. 648,P = 0. 010) and HVPG value at the second time of measurement( HR = 1. 481,95% CI: 1. 102-1. 990,P = 0. 009) were independent risk factors for EGVB. Conclusion The rate of hemodynamic response in cirrhotic patients with esophageal and gastric varices is 43. 75% after short-term oral administration of propranolol. Responders have a significantly lower risk of EGVB than non-responders. Patients with a past history of bleeding or a high HVPG value at the second time of measurement have an increased risk of bleeding.
Objective To investigate whether short-term oral administration of propranolol can induce hemodynamic response in patients with liver cirrhosis and esophageal and gastric varices,as well as the clinical significance of such response in the prevention of esophagogastric variceal bleeding( EGVB). Methods A total of 42 cirrhotic patients with esophageal and gastric varices who were treated in Department of Gastroenterology in Affiliated Drum Tower Hospital of Nanjing University Medical School from March 2015 to October 2016 were enrolled. Hepatic venous pressure gradient( HVPG) was measured before and after 7 days of oral administration of propranolol. The patients who completed these two HVPG measurements were followed up until the development of EGVB. Hemodynamic response was defined as a reduction in HVPG by at least 20% or an absolute value of HVPG of ≤12 mm Hg. The paired samples t-test and the chi-square test were used to compare the change in HVPG after propranolol administration and the incidence of EGVB between responders and non-responders.A regression analysis was used to identify the independent risk factors for EGVB. Results A total of 32 patients were included in the final analysis,with an overall response rate of 43. 75%( 14 responders and 18 non-responders),and the overall HVPG value decreased from18. 3 ± 5. 0 mm Hg to 15. 0 ± 4. 9 mm Hg( t = 4. 640,P < 0. 001). There were no significant differences in age,sex,etiology,liver function,and baseline HVPG between the responders and the non-responders( all P > 0. 05),and the responders had a significantly higher HVPG value at the second time of measurement than the non-responders( 11. 5 ± 3. 5 mm Hg vs 17. 7 ± 5. 0 mm Hg,t = 5. 470,P <0. 001). During the 3-year follow-up,8 patients developed EGVB,and the responders had a significantly lower incidence rate of EGVB than the non-responders( χ2= 8. 529,P = 0. 004). The multivariate Cox regression analysis showed that a past history of bleeding( hazard ratio [HR]= 12. 917,95% confidence interval [CI]: 1. 861-89. 648,P = 0. 010) and HVPG value at the second time of measurement( HR = 1. 481,95% CI: 1. 102-1. 990,P = 0. 009) were independent risk factors for EGVB. Conclusion The rate of hemodynamic response in cirrhotic patients with esophageal and gastric varices is 43. 75% after short-term oral administration of propranolol. Responders have a significantly lower risk of EGVB than non-responders. Patients with a past history of bleeding or a high HVPG value at the second time of measurement have an increased risk of bleeding.
引文
[1]GARCIA-TSAO G,BOSCH J. Management of varices and variceal hemorrhage in cirrhosis[J]. N Engl J Med,2011,362(9):823-832.
[2]GARCIA-TSAO G,BOSCH J. Varices and variceal hemorrhage in cirrhosis:A new view of an old problem[J]. Clin Gastroenterol Hepatol,2015,13(12):2109-2117.
[3]BOSCH J,GARCIA-PAGAN JC. Prevention of variceal rebleeding[J]. Lancet,2003,361(361):952-954.
[4]LIN YQ,JIANG B,LI HQ,et al. Application of hepatic transit time in portal vein pressure assessment in patients with portal hypertension and esophago gastric varices[J]. J Jilin Univ:Med Edit,2019,45(1):170-174.(in Chinese)林元强,姜博,李鹤群,等.肝脏渡越时间在门静脉高压-食管胃底静脉曲张患者门静脉压力评估中的应用[J].吉林大学学报:医学版,2019,45(1):170-174.
[5]VOROBIOFF J,GROSZMANN RJ,PICABEA E,et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis:A 10-year prospective study[J]. Gastroenterology,1996,111(3):701-709.
[6]de FRACHIS R. Updating consensus in portal hypertension:Report of the Baveno III Consensus Workshop on definitions,methodology and therapeutic strategies in portal hypertension[J]. J Hepatol,2000,33(5):846-852.
[7]GROSZMANN RJ,BOSCH J,GRACE ND,et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage[J]. Gastroenterology,1990,99(5):1401-1407.
[8]GARCIA-TSAO G,GROSZMANN RJ,FISHER RL,et al. Portal pressure, presence of gastroesophageal varices and variceal bleeding[J]. Hepatology,1985,5(3):419-424.
[9]DAMICO G,GARCIA-PAGAN JC,LUCA A,et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis:A systematic review[J]. Gastroenterology,2006,131(5):1611-1624.
[10]ESCORELL A,BORDAS JM,CASTANEDA B,et al. Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension[J]. Hepatology,2000,31(5):1061-1067.
[11]FEU F,GARCIA-PAGAN JC,BOSCH J,et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis[J]. Lancet,1995,346(8982):1056-1059.
[12]MERKEL C,BOLOGNESI M,BERZIGOTTI A,et al. Clinical significance of worsening portal hypertension during longterm medical treatment in patients with cirrhosis who had been classified as early good-responders on haemodynamic criteria[J]. J Hepatol,2010,52(1):45-53.
[13]TURNES J,GARCIA-PAGAN JC,ABRALDES JG,et al. Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis[J]. Am J Gastroenterol,2006,101(3):506-512.
[14]de FRACHIS R. Revising consensus in portal hypertension:Report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension[J]. J Hepatol,2010,53(3):762-768.
[15]MERKEL C,BOLOGNESI M,SACERDOTI D,et al. Disagreement between acute and chronic haemodynamic effects of nadolol in cirrhosis:A pathophysiological interpretation[J].Aliment Pharmacol Ther,2005,22(5):433-439.
[16]VOROBIFF J,PICABEA E,VILLAVICENCIO R,et al. Acute and chronic hemodynamic effects of propranolol in unselected cirrhotic patients[J]. Hepatology,1987,7(4):648-653.
[17]ZHANG F,DUAN X,ZHANG M,et al. Influence of CYP2D6 andβ2-adrenergic receptor gene polymorphisms on the hemodynamic response to propranolol in Chinese Han patients with cirrhosis[J]. J Gastroenterol Hepatol,2016,31(4):829-834.
[18]BOSCH J,GARCIA-PAGAN JC,BERZIGOTTI A,et al. Measurement of portal pressure and its role in the management of chronic liver disease[J]. Semin Liver Dis,2006,26(4):348-362.
[19]DUAN XH,ZHUGE YZ,ZHANG F. Advances in study on preventive efficacy of non-selective beta-blockers in patients with esophageal gastric variceal bleeding[J]. Chin J Gastroenterol,2015,20(10):629-631.(in Chinese)段旭红,诸葛宇征,张峰.非选择性β受体阻滞剂预防食管胃静脉曲张破裂出血的研究进展[J].胃肠病学,2015,20(10):629-631.
[20]ABRALDES JG,TARANTINO I,TURNES J,et al. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis[J]. Hepatology,2003,37(4):902-908.
[21]MERKEL C,BOLOGNESI M,SACERDOTI D,et al. The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis[J]. Hepatology,2000,32(5):930-934.
[22]GROSZMANN RJ,GARCIA-TSAO G,BOSCH J. et al. Betablockers to prevent gastroesophageal varices in patients with cirrhosis[J]. N Engl J Med,2005,353(21):2254-2261.
[23]SARIN SK,MISHRA SR,SHARNA P,et al. Early primary prophylaxis with beta-blockers does not prevent the growth of small esophageal varices in cirrhosis:A randomized controlled trial[J].Hepatol Int,2013,7(1):248-256.
[24]BHARDWAJ A,KEDARISETTY CK,VASHISHTHA C,et al. Carvedilol delays the progression of smal oesophageal varices in patients with cirrhosis:A randomised placebo-controlled trial[J].Gut,2017,66(10):1838-1843.
[25]REIBERGER T,ULBRICH G,FERLITSCH A,et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol[J]. Gut,2013,62(11):1634-1641.
[26]BANARES R,MOITINHO E,PIQUERAS B,et al. Carvedilol,a new nonselective beta-blocker with intrinsic anti-alpha(1)-adrenergic activity,has a greater portal hypotensive effect than propranolol in patients with cirrhosis[J]. Hepatology,1999,30(1):79-83.
[27]GARCIA-TSAO G,GRACE ND,GROSMAN RJ,et al. Short-term effects of propranolol on portal venous-pressure[J].Hepatology,1986,6(1):101-106.
[28]DE-MADARIA E,PALAZON JM,HERNANDEZ FT,et al. Acute and chronic hemodynamic changes after propranolol in patients with cirrhosis under primary and secondary prophylaxis of variceal bleeding:A pilot study[J]. Eur J Gastroenterol Hepatol,2010,22(5):507-512.
[29]LA MURA V,ABRALDES JD,RAFFA S,et al. Prognostic value of acute hemodynamic response to i. v. propranolol in patients with cirrhosis and portal hypertension[J]. J Hepatol,2009,51(2):279-287.
[30]LIN FY,HUANG H,LU ML. Research advances in prognositic factors for patients with esophagogastirc variceal bleeding[J]. J Clin Hepatol,2018,34(11):2428-2432.(in Chinese)林凡榆,黄华,路明亮.食管胃静脉曲张破裂出血预后相关因素的研究进展[J].临床肝胆病杂志,2018,34(11):2428-2432.
[2]GARCIA-TSAO G,BOSCH J. Varices and variceal hemorrhage in cirrhosis:A new view of an old problem[J]. Clin Gastroenterol Hepatol,2015,13(12):2109-2117.
[3]BOSCH J,GARCIA-PAGAN JC. Prevention of variceal rebleeding[J]. Lancet,2003,361(361):952-954.
[4]LIN YQ,JIANG B,LI HQ,et al. Application of hepatic transit time in portal vein pressure assessment in patients with portal hypertension and esophago gastric varices[J]. J Jilin Univ:Med Edit,2019,45(1):170-174.(in Chinese)林元强,姜博,李鹤群,等.肝脏渡越时间在门静脉高压-食管胃底静脉曲张患者门静脉压力评估中的应用[J].吉林大学学报:医学版,2019,45(1):170-174.
[5]VOROBIOFF J,GROSZMANN RJ,PICABEA E,et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis:A 10-year prospective study[J]. Gastroenterology,1996,111(3):701-709.
[6]de FRACHIS R. Updating consensus in portal hypertension:Report of the Baveno III Consensus Workshop on definitions,methodology and therapeutic strategies in portal hypertension[J]. J Hepatol,2000,33(5):846-852.
[7]GROSZMANN RJ,BOSCH J,GRACE ND,et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage[J]. Gastroenterology,1990,99(5):1401-1407.
[8]GARCIA-TSAO G,GROSZMANN RJ,FISHER RL,et al. Portal pressure, presence of gastroesophageal varices and variceal bleeding[J]. Hepatology,1985,5(3):419-424.
[9]DAMICO G,GARCIA-PAGAN JC,LUCA A,et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis:A systematic review[J]. Gastroenterology,2006,131(5):1611-1624.
[10]ESCORELL A,BORDAS JM,CASTANEDA B,et al. Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension[J]. Hepatology,2000,31(5):1061-1067.
[11]FEU F,GARCIA-PAGAN JC,BOSCH J,et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis[J]. Lancet,1995,346(8982):1056-1059.
[12]MERKEL C,BOLOGNESI M,BERZIGOTTI A,et al. Clinical significance of worsening portal hypertension during longterm medical treatment in patients with cirrhosis who had been classified as early good-responders on haemodynamic criteria[J]. J Hepatol,2010,52(1):45-53.
[13]TURNES J,GARCIA-PAGAN JC,ABRALDES JG,et al. Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis[J]. Am J Gastroenterol,2006,101(3):506-512.
[14]de FRACHIS R. Revising consensus in portal hypertension:Report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension[J]. J Hepatol,2010,53(3):762-768.
[15]MERKEL C,BOLOGNESI M,SACERDOTI D,et al. Disagreement between acute and chronic haemodynamic effects of nadolol in cirrhosis:A pathophysiological interpretation[J].Aliment Pharmacol Ther,2005,22(5):433-439.
[16]VOROBIFF J,PICABEA E,VILLAVICENCIO R,et al. Acute and chronic hemodynamic effects of propranolol in unselected cirrhotic patients[J]. Hepatology,1987,7(4):648-653.
[17]ZHANG F,DUAN X,ZHANG M,et al. Influence of CYP2D6 andβ2-adrenergic receptor gene polymorphisms on the hemodynamic response to propranolol in Chinese Han patients with cirrhosis[J]. J Gastroenterol Hepatol,2016,31(4):829-834.
[18]BOSCH J,GARCIA-PAGAN JC,BERZIGOTTI A,et al. Measurement of portal pressure and its role in the management of chronic liver disease[J]. Semin Liver Dis,2006,26(4):348-362.
[19]DUAN XH,ZHUGE YZ,ZHANG F. Advances in study on preventive efficacy of non-selective beta-blockers in patients with esophageal gastric variceal bleeding[J]. Chin J Gastroenterol,2015,20(10):629-631.(in Chinese)段旭红,诸葛宇征,张峰.非选择性β受体阻滞剂预防食管胃静脉曲张破裂出血的研究进展[J].胃肠病学,2015,20(10):629-631.
[20]ABRALDES JG,TARANTINO I,TURNES J,et al. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis[J]. Hepatology,2003,37(4):902-908.
[21]MERKEL C,BOLOGNESI M,SACERDOTI D,et al. The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis[J]. Hepatology,2000,32(5):930-934.
[22]GROSZMANN RJ,GARCIA-TSAO G,BOSCH J. et al. Betablockers to prevent gastroesophageal varices in patients with cirrhosis[J]. N Engl J Med,2005,353(21):2254-2261.
[23]SARIN SK,MISHRA SR,SHARNA P,et al. Early primary prophylaxis with beta-blockers does not prevent the growth of small esophageal varices in cirrhosis:A randomized controlled trial[J].Hepatol Int,2013,7(1):248-256.
[24]BHARDWAJ A,KEDARISETTY CK,VASHISHTHA C,et al. Carvedilol delays the progression of smal oesophageal varices in patients with cirrhosis:A randomised placebo-controlled trial[J].Gut,2017,66(10):1838-1843.
[25]REIBERGER T,ULBRICH G,FERLITSCH A,et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol[J]. Gut,2013,62(11):1634-1641.
[26]BANARES R,MOITINHO E,PIQUERAS B,et al. Carvedilol,a new nonselective beta-blocker with intrinsic anti-alpha(1)-adrenergic activity,has a greater portal hypotensive effect than propranolol in patients with cirrhosis[J]. Hepatology,1999,30(1):79-83.
[27]GARCIA-TSAO G,GRACE ND,GROSMAN RJ,et al. Short-term effects of propranolol on portal venous-pressure[J].Hepatology,1986,6(1):101-106.
[28]DE-MADARIA E,PALAZON JM,HERNANDEZ FT,et al. Acute and chronic hemodynamic changes after propranolol in patients with cirrhosis under primary and secondary prophylaxis of variceal bleeding:A pilot study[J]. Eur J Gastroenterol Hepatol,2010,22(5):507-512.
[29]LA MURA V,ABRALDES JD,RAFFA S,et al. Prognostic value of acute hemodynamic response to i. v. propranolol in patients with cirrhosis and portal hypertension[J]. J Hepatol,2009,51(2):279-287.
[30]LIN FY,HUANG H,LU ML. Research advances in prognositic factors for patients with esophagogastirc variceal bleeding[J]. J Clin Hepatol,2018,34(11):2428-2432.(in Chinese)林凡榆,黄华,路明亮.食管胃静脉曲张破裂出血预后相关因素的研究进展[J].临床肝胆病杂志,2018,34(11):2428-2432.