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Prevention and Management of Esophageal Variceal and Portal Hypertensive Hemorrhage Thomas Hargrave, M.D. March 24, 2012 Thomas Hargrave, M.D. March 24, 2012 Slide 2 Gastroesophageal Variceal Hemorrhage Gastroesophageal variceal hemorrhage is one of the major complications of portal hypertension from cirrhosis Variceal hemorrhage occurs in 25-35% of cirrhotics and accounts for 70-80% of UGIB in these patients. Aprroximately 50% of cirrhotics will have varices at the time of diagnosis 7-8% develop de novo varices each year Gastroesophageal variceal hemorrhage is one of the major complications of portal hypertension from cirrhosis Variceal hemorrhage occurs in 25-35% of cirrhotics and accounts for 70-80% of UGIB in these patients. Aprroximately 50% of cirrhotics will have varices at the time of diagnosis 7-8% develop de novo varices each year Slide 3 Prevalence and Size of Esophageal Varices in Patients with Newly-Diagnosed Cirrhosis % Patients with varices % Patients with varices 100 60 40 20 0 0 Overall n=494 Overall n=494 Child A n=346 Child A n=346 Child B n=114 Child B n=114 80 Child C n=34 Child C n=34 Large Medium Small Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72 PREVALENCE AND SIZE OF ESOPHAGEAL VARICES IN PATIENTS WITH NEWLY DIAGNOSED CIRRHOSIS Slide 4 Gastroesophageal Variceal Hemorrhage The 1-year risk of a first variceal hemorrhage is approximately 12% (5% for small varices and 15% for large varices). The 6-week mortality with each episode of variceal hemorrhage is approximately 15 -20%, From 0% among patients with Child class A disease to 30% among patients with Child class C disease. The 1-year rate of recurrent variceal hemorrhage is approximately 60%. The 1-year risk of a first variceal hemorrhage is approximately 12% (5% for small varices and 15% for large varices). The 6-week mortality with each episode of variceal hemorrhage is approximately 15 -20%, From 0% among patients with Child class A disease to 30% among patients with Child class C disease. The 1-year rate of recurrent variceal hemorrhage is approximately 60%. Slide 5 Portal Venous Anatomy Pathophysiology Slide 6 Slide 7 Hepatic/Portal Blood Flow Blood accounts for 25-30% of the volume of the liver Total Hepatic Blood Flow: Hepatic arterial and portal venous blood flow Approximately 25% of the cardiac output Males: 1860 cc/min Females: 1550 cc/min Portal venous blood flow averages 1500 cc/min Normal portal venous pressure is 4-8 mmHg Blood accounts for 25-30% of the volume of the liver Total Hepatic Blood Flow: Hepatic arterial and portal venous blood flow Approximately 25% of the cardiac output Males: 1860 cc/min Females: 1550 cc/min Portal venous blood flow averages 1500 cc/min Normal portal venous pressure is 4-8 mmHg Slide 8 Hepatic Lobular Anatomy Slide 9 Pathophysiology Gastroesophageal varices are a direct consequence of portal hypertension that, in cirrhosis, results from Increased resistance to portal flow Structural (distortion of liver vascular architecture by fibrosis and regenerative nodules) and Dynamic (increased hepatic vascular tone due to endothelial dysfunction and decreased nitric oxide bioavailability). Increased portal venous blood inflow. Gastroesophageal varices are a direct consequence of portal hypertension that, in cirrhosis, results from Increased resistance to portal flow Structural (distortion of liver vascular architecture by fibrosis and regenerative nodules) and Dynamic (increased hepatic vascular tone due to endothelial dysfunction and decreased nitric oxide bioavailability). Increased portal venous blood inflow. Slide 10 Intracellular Spaces (of Disse) in the Portal Sinusoids Large Enough for Chylomicroms to Pass Slide 11 Slide 12 Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:823-832. Slide 13 Slide 14 A Threshold Portal Pressure of ~12 mmHg is Necessary for Esophageal Varices to Form P % Rebleeding % Rebleeding Decrease In Hepatic Venous Pressure Gradient (HVPG) Reduces Risk of Variceal Bleeding 0 0 20 40 60 80 100 HVPG decrease > 20% from baseline HVPG decrease > 20% from baseline HVPG decrease to < 12 mmHg 0% 46-65% 7-13% No change in HVPG No change in HVPG Bosch and Garca-Pagn, Lancet 2003; 361:952 DECREASE IN HEPATIC VENOUS PRESSURE GRADIENT (HVPG) REDUCES THE RISK OF VARICEAL BLEEDING Slide 29 Primary Prophylaxis for Variceal Hemorrhage: Beta Blockers Non-selective beta-blockers preferred Beta-1 antagonism: reduced cardiac output Beta-2 antagonism: splanchnic vasoconstriction Goal of therapy to reduce portal pressure by 20% or below 12 mm Hg Dose titrated to a resting HR of 55, or a 25% reduction in baseline Initial dose propranolol 40 mg bid, Average dose 160 mg/day Up to 1/3 intolerant to side effects resulting in discontinuation Non-selective beta-blockers preferred Beta-1 antagonism: reduced cardiac output Beta-2 antagonism: splanchnic vasoconstriction Goal of therapy to reduce portal pressure by 20% or below 12 mm Hg Dose titrated to a resting HR of 55, or a 25% reduction in baseline Initial dose propranolol 40 mg bid, Average dose 160 mg/day Up to 1/3 intolerant to side effects resulting in discontinuation Slide 30 Non-Selective Beta-Blockers Prevent First Variceal Hemorrhage: 11 Trials Bleeding rateControlBeta-blockerAbsolute rate (~2 year) difference All varices25%15%-10% (11 trials)(n=600)(n=590)(-16 to -5) Large varices30% 14% -16% (8 trials)(n=411)(n=400) (-24 to -8) Small varices7%2%-5% (3 trials)(n=100)(n=91)(-11 to 2) Bleeding rateControlBeta-blockerAbsolute rate (~2 year) difference All varices25%15%-10% (11 trials)(n=600)(n=590)(-16 to -5) Large varices30% 14% -16% (8 trials)(n=411)(n=400) (-24 to -8) Small varices7%2%-5% (3 trials)(n=100)(n=91)(-11 to 2) DAmico et al., Sem Liv Dis 1999; 19:475 NON-SELECTIVE BETA-BLOCKERS PREVENT FIRST VARICEAL HEMORRHAGE Slide 31 Primary Prophylaxis against Variceal Hemorrhage. Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:823-832. Slide 32 Garca-Pagn et al., Hepatology 2003; 37:1260 The Risk of First Bleeding is Not Reduced by Adding Isosorbide Mononitrate (ISMN) to -blockers % % 100 50 0 0 25 1 1 75 Years 2 2 100 50 0 0 25 1 1 75 Years 2 2 ns Free of a first variceal bleeding Survival Propranolol + ISMN Propranolol + placebo Propranolol + ISMN Propranolol + placebo THE RISK OF FIRST VARICEAL HEMORRHAGE IS NOT REDUCED BY ADDING ISOSORBIDE MONONITRATE (ISMN) TO BETA-BLOCKERS Slide 33 Endoscopic Variceal Band Ligation ENDOSCOPIC VARICEAL BAND LIGATION Slide 34 Primary Prophylaxis for Variceal Hemorrhage 3 randomized controlled trials published comparing band ligation to no treatment, showing lower bleeding rates and mortality. Meta-analysis of 8 trial show banding superior to beta blockers but no difference in survival One trial of band ligation and beta blockers: no benefit Prophylactic sclerotherapy definitely of no proven benefit, probably harmful. 3 randomized controlled trials published comparing band ligation to no treatment, showing lower bleeding rates and mortality. Meta-analysis of 8 trial show banding superior to beta blockers but no difference in survival One trial of band ligation and beta blockers: no benefit Prophylactic sclerotherapy definitely of no proven benefit, probably harmful. Slide 35 Variceal Band Ligation (VBL) vs. Beta-Blockers (BB) in the Prevention of First Variceal Bleed Khuroo, et al., Aliment Pharmacol Ther 2005; 21:347 First hemorrhage Survival Chen 1998 Sarin 1999 De 1999 Jutabha2000 De la Mora 2000 Lui 2002 Lo 2004 Schepke 2004 Total Chen 1998 Sarin 1999 De 1999 Jutabha2000 De la Mora 2000 Lui 2002 Lo 2004 Schepke 2004 Total Relative risk 0 0 1 1 10 0 0 1 1 40 Favors VBL Favors BB VARICEAL BAND LIGATION (VBL) VS. BETA-BLOCKERS (BB) IN THE PREVENTION OF FIRST VARICEAL HEMORRHAGE Slide 36 Prophylaxis of Variceal Hemorrhage Diagnosis of Cirrhosis Endoscopy No Varices Follow-up EGD in 2-3 years* Small Varices Follow-up EGD in 1-2 years* Medium/Large Varices Childs C or Stigmata Medium/Large Varices Childs C or Stigmata Stepwise increase until maximally tolerated dose Continue beta-blocker (life-long) No role for repeated endoscopy!! Stepwise increase until maximally tolerated dose Continue beta-blocker (life-long) No role for repeated endoscopy!! No Contraindications Contraindications or Beta-blocker intolerance Contraindications or Beta-blocker intolerance Beta-blocker therapy Endoscopic Variceal Band Ligation *EGD every year in decompensated cirrhosis MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARY No role for sclerotherapy or nitrates Slide 37 Primary Prophylaxis for Variceal Hemorrhage: Conclusions Propranolol is the most cost-effective treatment for the prevention of initial variceal bleeding The documented benefits of prophylactic beta blockers may be lost if discontinued due to a rebound in bleeding/ mortality. Life-long beta blocker treatment is therefore indicated Non-compliant patients may be better served by band ligation therapy, although at substantially higher costs ($1425 vs $4284) Propranolol is the most cost-effective treatment for the prevention of initial variceal bleeding The documented benefits of prophylactic beta blockers may be lost if discontinued due to a rebound in bleeding/ mortality. Life-long beta blocker treatment is therefore indicated Non-compliant patients may be better served by band ligation therapy, although at substantially higher costs ($1425 vs $4284) Hepatology 2001; 34(6):1096-02 Slide 38 Management of Variceal Bleeding Primary Prophylaxis Pharmacologic Endoscopic Acute Variceal Hemorrhage Pharmacologic Endoscopic TIPS Secondary Prophylaxis Pharmcologic Endoscopic TIPS Primary Prophylaxis Pharmacologic Endoscopic Acute Variceal Hemorrhage Pharmacologic Endoscopic TIPS Secondary Prophylaxis Pharmcologic Endoscopic TIPS Slide 39 Treatment of Acute Variceal Hemorrhage General Management: IV access and fluid resuscitation Antibiotic prophylaxis Correct coagulopathy Do not overtransfuse (hemoglobin ~ 7-8 g/dL) Empiric lactulose? Specific therapy: Pharmacological therapy: octreotide, vasopressin + nitroglycerin Early endoscopic therapy: band ligation Shunt therapy: TIPS, surgical shunt General Management: IV access and fluid resuscitation Antibiotic prophylaxis Correct coagulopathy Do not overtransfuse (hemoglobin ~ 7-8 g/dL) Empiric lactulose? Specific therapy: Pharmacological therapy: octreotide, vasopressin + nitroglycerin Early endoscopic therapy: band ligation Shunt therapy: TIPS, surgical shunt TREATMENT OF ACUTE VARICEAL HEMORRHAGE Slide 40 Cautious Transfusion Improves Outcome in Cirrhotics with Variceal Hemorrhage 214 cirrhotics with UGIB randomized to restricted (Hgb 7-8 gm) or liberal transfusion (Hgb 9-10 gm) 69% esophageal variceal 7% gastric variceal 15% peptic ulcer 3% gastropathy Therapeutic failure occurred in 16% of restricted and 28% of liberal group (p Phamacologic Treatment for Acute Variceal Hemorrhage Octreotide: 50 microgram bolus and 25-50 mcg/hr for up to 5 days (range 2-5 days) Vasopressin: Too dangerous for empiric initial therapy Contiunuous infusion 0.2-0.4 U/min up to 1.0 U/min Recommended only in combination with i.v. TNG: 10- 50 mcg/min Titrate TNG infusion to maintain systolic BP >90 mmHg Continuous vasopressin> 24 hr not recommended Octreotide: 50 microgram bolus and 25-50 mcg/hr for up to 5 days (range 2-5 days) Vasopressin: Too dangerous for empiric initial therapy Contiunuous infusion 0.2-0.4 U/min up to 1.0 U/min Recommended only in combination with i.v. TNG: 10- 50 mcg/min Titrate TNG infusion to maintain systolic BP >90 mmHg Continuous vasopressin> 24 hr not recommended Slide 46 Lactulose 30 mL TID_QID until pts had non-melenic stools and then the dose was reduced so that patients had two to three semiformed stools per day Prophylaxis of HSE in Acute Variceal Bleed Slide 47 Endoscopic Therapy Now Standard in the Management of Variceal Hemorrhage PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE Slide 48 Non-Pharmacologic Treatment of Acute Variceal Hemorrhage Endoscopic Band Ligation Transjugular Intrahepatic Portal- systemic Shunting (TIPS) Mostly Historical Interest Sengstaken-Blakemore Tube Embolization of varices Portacaval shunt surgery Injection Sclerotherapy Endoscopic Band Ligation Transjugular Intrahepatic Portal- systemic Shunting (TIPS) Mostly Historical Interest Sengstaken-Blakemore Tube Embolization of varices Portacaval shunt surgery Injection Sclerotherapy Slide 49 Endoscopic Variceal Band Ligation Bleeding controlled in 90% Rebleeding rate 30% Compared with sclerotherapy: Less rebleeding Lower mortality Fewer complications Fewer treatment sessions Bleeding controlled in 90% Rebleeding rate 30% Compared with sclerotherapy: Less rebleeding Lower mortality Fewer complications Fewer treatment sessions ENDOSCOPIC VARICEAL BAND LIGATION Slide 50 Slide 51 Erythromycin improves visibility during endoscopy for variceal bleeding Study involved 90 patients with cirrhosis who had been vomiting blood due to variceal bleeding during the previous 12 hours. The 47 patients randomized to the intervention group received an intravenous bolus infusion of 125 mg erythromycin lactobionate in 50 mL normal saline. The other 43 patients received only the saline. (All patients also received octreotide, esmoprazole, and ceftriaxone.) Study involved 90 patients with cirrhosis who had been vomiting blood due to variceal bleeding during the previous 12 hours. The 47 patients randomized to the intervention group received an intravenous bolus infusion of 125 mg erythromycin lactobionate in 50 mL normal saline. The other 43 patients received only the saline. (All patients also received octreotide, esmoprazole, and ceftriaxone.) Gastrointest Endosc 2010. Slide 52 Erythromycin improves visibility during endoscopy for variceal bleeding On multivariate analysis, erythromycin was the only predictor of an empty stomach. As a result, the average time needed for endoscopy was also shorter after erythromycin (19 vs 26 min, p < 0.005). Physicians found that with erythromycin, they could control bleeding by band ligation more often (70% vs 49%, p < 0.04) and that hospital stays were shorter (3.4 vs 5.1 days, p < 0.002). On multivariate analysis, erythromycin was the only predictor of an empty stomach. As a result, the average time needed for endoscopy was also shorter after erythromycin (19 vs 26 min, p < 0.005). Physicians found that with erythromycin, they could control bleeding by band ligation more often (70% vs 49%, p < 0.04) and that hospital stays were shorter (3.4 vs 5.1 days, p < 0.002). Gastrointest Endosc 2010. Slide 53 Baares R et al., Hepatology 2002; 35:609 Combination Drug / Endoscopic Therapy is More Effective Than Endoscopic Therapy Alone in Achieving Five-Day Hemostasis Sclero + OctreotideBesson, 1995 Ligation + Octreotide Sung, 1995 Sclero + Octreotide / STSignorelli, 1996 Sclero + Octreotide Ceriani, 1997 Sclero + Octreotide Signorelli, 1997 Sclero + STAvgerinos, 1997 Sclero + Octreotide Zuberi, 2000 Sclero / ligation + VapreotideCales, 2001 TOTAL Sclero + OctreotideBesson, 1995 Ligation + Octreotide Sung, 1995 Sclero + Octreotide / STSignorelli, 1996 Sclero + Octreotide Ceriani, 1997 Sclero + Octreotide Signorelli, 1997 Sclero + STAvgerinos, 1997 Sclero + Octreotide Zuberi, 2000 Sclero / ligation + VapreotideCales, 2001 TOTAL Favors endoscopic therapy alone 1 1 1.6 1.8 2 2 1.2 1.4 0.8 Favors endoscopic plus drug therapy Relative Risk COMBINATION DRUG/ENDOSCOPIC THERAPY IS MORE EFFECTIVE THAN ENDOSCOPIC THERAPY ALONE No Mortality Difference Slide 54 Transjugular Intrahepatic Portosystemic Shunt Hepatic vein Hepatic vein Portal vein Splenic vein Splenic vein Superior mesenteric vein TIPS THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT Slide 55 TIPS in the Treatment of Variceal Hemorrhage TIPS is rescue therapy for recurrent variceal hemorrhage (at second rebleed for esophageal varices, at first rebleed for gastric varices) TIPS is indicated in patients who rebleed on combination endoscopic plus pharmacologic therapy (10-20%) In patients with Child A/B cirrhosis, the distal spleno-renal shunt is as effective as TIPS (dependent on local expertise) TIPS is rescue therapy for recurrent variceal hemorrhage (at second rebleed for esophageal varices, at first rebleed for gastric varices) TIPS is indicated in patients who rebleed on combination endoscopic plus pharmacologic therapy (10-20%) In patients with Child A/B cirrhosis, the distal spleno-renal shunt is as effective as TIPS (dependent on local expertise) TIPS IN THE TREATMENT OF VARICEAL HEMORRHAGE Slide 56 116 cirrhotics with acute variceal bleed Urgent assessment of wedged hepatic vein pressure 64 HVPG < 20 mmHg: routine therapy 52 HVPG > 20 mmHg randomized to TIPS vs routine therapy Early TIPS in patients with HVPG>20 associated with reduced transfusion, rebleed, in-hospital and 1 year mortality 116 cirrhotics with acute variceal bleed Urgent assessment of wedged hepatic vein pressure 64 HVPG < 20 mmHg: routine therapy 52 HVPG > 20 mmHg randomized to TIPS vs routine therapy Early TIPS in patients with HVPG>20 associated with reduced transfusion, rebleed, in-hospital and 1 year mortality Early TIPS In Patients With Acute Variceal Hemorrhage and HVPG > 20 mmHg (High Risk) May Improve Survival Monescillo et al., Hepatology 2004; 40:793 Slide 57 Early TIPS In Patients With Acute Variceal Hemorrhage and HVPG > 20 mmHg (High Risk) May Improve Survival 0 0 0.2 0.4 0.6 0.8 1 1 0 0 12 9 9 6 6 3 3 HVPG 20 - TIPS HVPG >20 No TIPS Probability of survival Monescillo et al., Hepatology 2004; 40:793 Months EARLY TIPS IN PATIENTS WITH ACUTE VARICEAL HEMORRHAGE AND HVPG > 20 mmHg MAY IMPROVE SURVIVAL Slide 58 Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy Randomized to treatment with a polytetrafluoroethylene- covered stent within 72 hours after randomization (early-TIPS group, 32 patients) Vs continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapyEBL group, 31 patients). 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy Randomized to treatment with a polytetrafluoroethylene- covered stent within 72 hours after randomization (early-TIPS group, 32 patients) Vs continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapyEBL group, 31 patients). Garca-Pagn JC et al. N Engl J Med 2010;362:2370-2379. Slide 59 Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding Slide 60 During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapyEBL group as compared with 1 patient in the early-TIPS group (P=0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapyEBL group versus 97% in the early-TIPS group (P