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80 Thomas Hargrave, M.D. March 24, 2012 Prevention and Management of Esophageal Variceal and Portal Hypertensive HemorrhageThomas Hargrave, M.D.March 24, 2012
81 Gastroesophageal Variceal Hemorrhage Gastroesophageal variceal hemorrhage is one of the major complications of portal hypertension from cirrhosisVariceal 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 diagnosis7-8% develop de novo varices each year
82 PREVALENCE AND SIZE OF ESOPHAGEAL VARICES IN PATIENTS WITH NEWLY DIAGNOSED CIRRHOSIS 10080Large%Patients with varices6040MediumSlide 84PREVALENCE AND SIZE OF ESOPHAGEAL VARICES IN PATIENTS WITH NEWLY DIAGNOSED CIRRHOSISEsophageal varices are present in approximately half of the patients with cirrhosis. The prevalence correlates to the severity of liver disease with Child C cirrhotic patients being twice as likely to have varices as Child A patients. In addition, Child C patients are more likely to have large varices than patients with less severe liver disease.Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994; 7220SmallOveralln=494Child An=346Child Bn=114Child Cn=34Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72
83 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 %,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%.
86 Hepatic/Portal Blood Flow Blood accounts for 25-30% of the volume of the liverTotal Hepatic Blood Flow: Hepatic arterial and portal venous blood flowApproximately 25% of the cardiac outputMales: 1860 cc/minFemales: 1550 cc/minPortal venous blood flow averages 1500 cc/minNormal portal venous pressure is 4-8 mmHg
88 PathophysiologyGastroesophageal varices are a direct consequence of portal hypertension that, in cirrhosis, results fromIncreased resistance to portal flowStructural (distortion of liver vascular architecture by fibrosis and regenerative nodules) andDynamic (increased hepatic vascular tone due to endothelial dysfunction and decreased nitric oxide bioavailability).Increased portal venous blood inflow.
89 Intracellular Spaces (of Disse) in the Portal Sinusoids Large Enough for Chylomicroms to Pass
91 Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:823-832. Figure 1. The Pathogenesis of Portal Hypertension, Varices, and Variceal Hemorrhage. The initial mechanism in the development of portal hypertension in cirrhosis is an increase in vascular resistance to portal flow. A subsequent increase in portal venous inflow maintains the portal hypertensive state. Portal hypertension leads to the formation of portosystemic collaterals, of which the most clinically relevant are gastroesophageal varices. The increase in flow through these collaterals, enhanced by the presence of splanchnic vasodilatation and increased portal blood inflow, leads to variceal growth and rupture. This process is modulated by angiogenic factors. VEGF denotes vascular endothelial growth factor.Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:
92 Portal venous blood flow observed Portal venous blood flow observed with esophageal and gastric varices. (Adapted from Kitano et al. 
93 A THRESHOLD PORTAL PRESSURE OF ~12 mmHg IS NECESSARY FOR VARICES TO FORM A Threshold Portal Pressure of ~12 mmHg is Necessary for Esophageal Varices to FormVarices Present(n=72)Varices Absent(n=15)3530HepaticVenousPressureGradient(mmHg)2520P<0.01Slide 85A THRESHOLD PORTAL PRESSURE OF ~12 mmHg IS NECESSARY FOR VARICES TO FORMInitial dilatation of the esophageal collaterals depends on a threshold portal pressure below which varices do not develop. This threshold has been established at an hepatic venous pressure gradient (HVPG) of mmHg. Notably, patients with no varices may have an HVPG >12 mmHg. Therefore the threshold HVPG level is necessary but not sufficient for the development of gastroesophageal varices. Factors other than pressure, such as volume of blood flow and local anatomic factors may contribute to the formation of varices.Garcia-Tsao et al., Hepatology 1985; 5: 4191512105Garcia-Tsao et. al., Hepatology 1985; 5:419
94 Venous Layers of the Esophagus Venous layers of the esophagus Venous layers of the esophagus. There are threeparts of the venous system related to the esophagus: intrinsic veins, associatedveins, and extrinsic veins. The two layers of veins in the wall of the esophagusare the superficial venous plexus (located in the lamina propria and muscularismucosa) and the submucosal plexus (within the circular muscle). In the distalesophagus, venous blood drains first from a superficial mucosal network of smallintraepithelial blood vessels into submucosal, longitudinally oriented deepintrinsic veins. Once in the intrinsic veins, blood drains through a system oftransverse perforating veins with unidirectional valves into extrinsic serosaland periesophageal veins and ultimately into the left gastric vein inferiorlyand the azygos vein superiorly. (Adapted from Kitano et al. 
95 VARICES INCREASE IN DIAMETER PROGRESSIVELY Slide 82VARICES INCREASE IN DIAMETER PROGRESSIVELYBoth development of varices and growth of small varices occurs at a rate of 7-8% per year. Although there are no identified clinical predictors for the development of varices, factors associated with variceal growth are Child B/C cirrhosis, alcoholic etiology and presence of red wale marks on initial endoscopy.Merli et al., J Hepatol 2003; 38: 266No varicesSmall varicesLarge varices7-8%/year7-8%/yearMerli et al. J Hepatol 2003;38:266
97 LARGE VARICES ARE MORE LIKELY TO RUPTURE No Varices100p<0.01 *Small Varices75%Patients without bleedingLarge Varices * *502-year probability of first bleed:Small varices: 7%Large varices: 30%Slide 98LARGE VARICES ARE MORE LIKELY TO RUPTUREThe most important predictor of variceal hemorrhage is variceal size. The incidence of first variceal hemorrhage in patients with small varices is very small , at ~5% per year, while large varices bleed at a rate of ~15% per year.Merli M, et al. J Hepatol 2003; 38: 266Conn HO, et al. Hepatology 1991; 13: 90225122412362436Time (months)*Merli et al., Hepatol 2003; 38:266, **Conn et al., Hepatology 1991; 13:902
98 Varix with red wale sign PunctumVariceal hemorrhageVarix with red wale sign
99 Management of Variceal Bleeding Primary ProphylaxisPharmacologicEndoscopicAcute Variceal HemorrhageTIPSSecondary ProphylaxisPharmcologic
100 Primary ProphylaxisIn view of the relatively high rate of bleeding from esophageal varices and the high associated mortality, an important goal of management of patients with cirrhosis is the primary prevention of variceal hemorrhage.As a result, all patients with cirrhosis should undergo diagnostic endoscopy to document the presence of varices and to determine their risk for variceal hemorrhage.
102 MANAGEMENT OF PATIENTS WITHOUT VARICES Treatment of Varices / Variceal HemorrhageCan we prevent formation of varices ?No varicesVaricesNo hemorrhageVaricealhemorrhageSlide 112MANAGEMENT OF PATIENTS WITHOUT VARICESIn cirrhotic patients who have not yet developed varices, no specific therapy is recommended. However, a surveillance endoscopy should be performed every 2-3 years in compensated cirrhosis and annually in decompensated cirrhosis.Recurrenthemorrhage
103 NON-SELECTIVE BETA BLOCKERS DO NOT PREVENT DEVELOPMENT OF VARICES Prevention of Esophageal Varices w/ Beta-Blockers?Multicenter, randomized, placebo-controlled trial of timolol (non-selective beta-blocker) vs. placebo in patientsBeta-blockers did not prevent the development of varices and were associated with a higher rate of serious adverse eventsIn patients without varices, treatment with nonselective beta-blockers is not recommendedSlide 111NON-SELECTIVE BETA BLOCKERS DO NOT PREVENT DEVELOPMENT OF VARICESIn a prospective randomized, placebo-controlled trial performed in patients with cirrhosis and portal hypertension (HVPG >5 mmHg) but without varices at baseline, the development of gastroesophageal varices was the same in patients randomized to a non-selective beta-blocker (timolol) compared to those randomized to placebo. Additionally, patients randomized to timolol had significantly greater number of serious adverse events compared to patients in the placebo group.The study demonstrates that a baseline HVPG of greater than 10 mmHg is the strongest predictor of the development of varices.Groszmann RJ, et al., Hepatology 2003; 38(suppl 1): 206AGroszmann, et al., Hepatology 2003;38 (suppl 1):206A
104 MANAGEMENT OF PATIENTS WITHOUT VARICES Treatment of Varices / Variceal HemorrhageNo specific therapyRepeat endoscopy in 2-3 yrs*No varicesVaricesNo hemorrhageVaricealhemorrhageSlide 112MANAGEMENT OF PATIENTS WITHOUT VARICESIn cirrhotic patients who have not yet developed varices, no specific therapy is recommended. However, a surveillance endoscopy should be performed every 2-3 years in compensated cirrhosis and annually in decompensated cirrhosis.Recurrenthemorrhage* Sooner with cirrhosis decompensation
105 PREVENTION OF FIRST VARICEAL HEMORRHAGE Treatment of Varices / Variceal HemorrhageNo varicesVaricesNo hemorrhagePrevention of first variceal hemorrhageVaricealhemorrhageSlide 113PREVENTION OF FIRST VARICEAL HEMORRHAGEThe second stage in the management of varices/variceal hemorrhage is constituted by patients with varices who have never bled from them. Can the first episode of variceal hemorrhage be prevented in these patients?Recurrenthemorrhage
107 HVPG decrease to < 12 mmHg DECREASE IN HEPATIC VENOUS PRESSURE GRADIENT (HVPG) REDUCES THE RISK OF VARICEAL BLEEDINGDecrease In Hepatic Venous Pressure Gradient (HVPG) Reduces Risk of Variceal Bleeding1008046-65%60%Rebleeding40Slide 102DECREASE IN HEPATIC VENOUS PRESSURE GRADIENT (HVPG) REDUCES THE RISK OF VARICEAL BLEEDINGEvidence from various randomized clinical trials of secondary prophylaxis of variceal hemorrhage and summarized in this slide confirms that reducing portal pressure results in a decreased risk of variceal hemorrhage. A decrease in HVPG to a level below 12 mmHg essentially eliminates the risk of recurrent variceal hemorrhage, while a reduction of at least 20% from baseline reduces this risk significantly (7-13%) compared to patients who do not achieve this reduction (rebleeding rate of 46-65%). Therefore, a rational goal of therapy of portal hypertension is to achieve a significant reduction in HVPG.Bosch and García-Pagán. Lancet 2003; 361:952207-13%0%HVPG decrease to < 12 mmHgHVPG decrease> 20% from baselineNo change inHVPGBosch and García-Pagán, Lancet 2003; 361:952
108 Primary Prophylaxis for Variceal Hemorrhage: Beta Blockers Non-selective beta-blockers preferredBeta-1 antagonism: reduced cardiac outputBeta-2 antagonism: splanchnic vasoconstrictionGoal of therapy to reduce portal pressure by 20%or below 12 mm HgDose titrated to a resting HR of 55, or a 25% reduction in baselineInitial dose propranolol 40 mg bid, Average dose 160 mg/dayUp to 1/3 intolerant to side effects resulting in discontinuation
109 NON-SELECTIVE BETA-BLOCKERS PREVENT FIRST VARICEAL HEMORRHAGE Non-Selective Beta-Blockers Prevent First Variceal Hemorrhage: 11 TrialsBleeding rate Control Beta-blocker Absolute rate(~2 year) differenceAll varices 25% 15% -10%(11 trials) (n=600) (n=590) (-16 to -5)Large varices 30% 14% -16%(8 trials) (n=411) (n=400) (-24 to -8)Small varices 7% 2% -5%(3 trials) (n=100) (n=91) (-11 to 2)Slide 115NON-SELECTIVE BETA-BLOCKERS PREVENT FIRST VARICEAL HEMORRHAGEA more recent meta-analysis of 11 randomized controlled trials of non-selective beta-adrenergic blockers for primary prophylaxis of variceal hemorrhage shows a significant lower 2-year risk of first variceal hemorrhage in patients treated with beta-blockers (15%) compared to controls (25%), with a greater benefit observed in patients with large varices. Although a small benefit was seen in patients with small varices, it did not reach statistical significance. There was a tendency for a survival benefit in patients treated with beta-blockers but this was not significant.D’Amico et al, Sem Liv Dis 1999; 19:475D’Amico et al., Sem Liv Dis 1999; 19:475
110 Primary Prophylaxis against Variceal Hemorrhage. Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:
111 Free of a first variceal bleeding THE RISK OF FIRST VARICEAL HEMORRHAGE IS NOT REDUCED BY ADDING ISOSORBIDE MONONITRATE (ISMN) TO BETA-BLOCKERSThe Risk of First Bleeding is Not Reduced by Adding Isosorbide Mononitrate (ISMN) to b-blockersFree of a first variceal bleedingSurvival100100nsns7575%5050Slide 116THE RISK OF FIRST VARICEAL HEMORRHAGE IS NOT REDUCED BY ADDING ISOSORBIDE MONONITRATE (ISMN) TO BETA-BLOCKERSIn a randomized controlled trial, neither the probability of developing first variceal hemorrhage nor the probability of survival were different between patients randomized to combination therapy propranolol +ISMN and those randomized to propanolol + placebo. Patients on combination therapy had a greater rate of side effects.Garcia-Pagan JC, et al. Hepatology 2003; 37:1260Propranolol + ISMNPropranolol + placeboPropranolol + ISMNPropranolol + placebo25251212YearsYearsGarcía-Pagán et al., Hepatology 2003; 37:1260
112 ENDOSCOPIC VARICEAL BAND LIGATION Slide 144ENDOSCOPIC VARICEAL BAND LIGATIONEndoscopic variceal ligation consists of the placement of rubber rings on variceal columns with the objective of interrupting blood flow and subsequently developing necrosis of mucosa and submucosa and replacement of varices by scar tissue. Endoscopic therapy is a local therapy that has no effect on the pathophysiologic mechanisms that lead to portal hypertension and variceal rupture. Even though it achieves variceal obliteration, varices will eventually recur. Bleeding is controlled in 90% of cases of acute variceal hemorrhage with a rebleeding rate of 30%. Meta-analysis of trials comparing ligation with sclerotherapy has shown that ligation is associated with lower rebleeding rates, lower number of sessions to achieve variceal obliteration and lower mortality. Complications of endoscopic therapy are related mainly to the development of esophageal ulceration and strictures, significantly more frequent after sclerotherapy than after ligation.Laine and Cook. Ann Intern Med 1995; 123:280
113 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 survivalOne trial of band ligation and beta blockers: no benefitProphylactic sclerotherapy definitely of no proven benefit, probably harmful.
114 VARICEAL BAND LIGATION (VBL) VS VARICEAL BAND LIGATION (VBL) VS. BETA-BLOCKERS (BB) IN THE PREVENTION OF FIRST VARICEAL HEMORRHAGEVariceal Band Ligation (VBL) vs. Beta-Blockers (BB) in the Prevention of First Variceal BleedFirst hemorrhageSurvivalChen 1998Sarin 1999De 1999Jutabha 2000De la Mora 2000Lui 2002Lo 2004Schepke 2004TotalRelative risk11040Favors VBLFavors BBFavors BBSlide 119VARICEAL BAND LIGATION (VBL) VS. BETA-BLOCKERS (BB) IN THE PREVENTION OF FIRST VARICEAL HEMORRHAGEIn a recent meta-analysis of 8 trials, VBL was shown to be more effective than beta-blockers in the primary prophylaxis of variceal hemorrhage with no differences in survival. However, these trials are small and have a relatively short followup time. The trial with the largest number of patients and the longest followup showed equivalence between both therapies.Khuroo, et al., Aliment Pharmacol Ther 2005; 21: 347Schepke et al. Hepatology 2004; 40:65Khuroo, et al., Aliment Pharmacol Ther 2005; 21:347
115 Prophylaxis of Variceal Hemorrhage MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARYProphylaxis of Variceal HemorrhageDiagnosis of CirrhosisEndoscopyNo VaricesFollow-up EGD in 2-3 years*Small VaricesFollow-up EGD in 1-2 years*Medium/Large VaricesChild’s C or StigmataStepwise increase until maximally tolerated doseContinue beta-blocker (life-long)No role for repeated endoscopy!!No ContraindicationsContraindicationsorBeta-blocker intoleranceBeta-blocker therapyEndoscopic Variceal Band Ligation*EGD every year in decompensated cirrhosisSlide 135MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARYNo role for sclerotherapy or nitrates
116 Primary Prophylaxis for Variceal Hemorrhage: Conclusions Propranolol is the most cost-effective treatment for the prevention of initial variceal bleedingThe 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 indicatedNon-compliant patients may be better served by band ligation therapy, although at substantially higher costs ($1425 vs $4284)Hepatology 2001; 34(6):
117 Management of Variceal Bleeding Primary ProphylaxisPharmacologicEndoscopicAcute Variceal HemorrhageTIPSSecondary ProphylaxisPharmcologic
118 TREATMENT OF ACUTE VARICEAL HEMORRHAGE General Management:IV access and fluid resuscitationAntibiotic prophylaxisCorrect coagulopathyDo not overtransfuse (hemoglobin ~ 7-8 g/dL)Empiric lactulose?Specific therapy:Pharmacological therapy: octreotide, vasopressin + nitroglycerinEarly endoscopic therapy: band ligationShunt therapy: TIPS, surgical shuntSlide 138TREATMENT OF ACUTE VARICEAL HEMORRHAGETreatment of acute variceal hemorrhage includes general and specific therapies. General management includes establishing intravenous access and fluid resuscitation. Vigorous fluid resuscitation and transfusion to hemoglobin levels >8 g/dL should be avoided as this could precipitate early variceal rebleeding. Prophylactic antibiotic therapy should be instituted promptly in any cirrhotic patient with gastrointestinal hemorrhage. Specific therapy includes pharmacological therapy, endoscopic therapy and shunt therapy.
119 Colomo A. et al , Abstract 232A (AASLD 2008) Cautious Transfusion Improves Outcome in Cirrhotics with Variceal Hemorrhage214 cirrhotics with UGIB randomized to restricted (Hgb 7-8 gm) or liberal transfusion (Hgb 9-10 gm)69% esophageal variceal 7% gastric variceal15% peptic ulcer % gastropathyTherapeutic failure occurred in 16% of restricted and 28% of liberal group (p<0.04)In subgroup with esophageal variceal bleed, the 6 week survival without therapeutic failure was better in restrictive group (84% vs 69%: p<0.02)38% in restrictive group required no transfusion vs 9% in liberal groupColomo A. et al , Abstract 232A (AASLD 2008)
120 Colomo A. et al , Abstract 232A (AASLD 2008) Cautious Transfusion Improves Outcome in Cirrhotics with Variceal HemorrhageP= 0.02P= 0.046-week survival in variceal bleeders who did not have therapeuticfailureColomo A. et al , Abstract 232A (AASLD 2008)
121 Prophylactic Antibiotics Improve Outcomes in Cirrhotic Patients with GI Hemorrhage The use of prophylactic antibiotics in cirrhotics with GI hemorrhage has been shown by meta-analysis to reduce infection, increase survival, and reduce recurrent hemorrhage (13 prospective trials)Recommended antibiotics include oral norfloxacin, ciprofloxin, ofloacin, and amoxicillin clavulanate, ceftriaxone IVSlide 139PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGEFive randomized controlled trials analyze the effect of prophylactic antibiotics (oral or systemic) in preventing bacterial infections in patients with cirrhosis admitted with gastrointestinal hemorrhage. A meta-analysis of these trials shows that prophylactic antibiotics not only reduce the risk of bacterial infections, including spontaneous bacterial peritonitis and spontaneous bacteremia, but also lead to a significant decrease in mortality. Therefore, the use of antibiotics is considered standard of care in this setting.Bernard B, et al., Hepatology 1999; 29: 1655Scand J. Gastro 2003;38:
122 Meta-analysis of 5 randomized trials PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGEProphylactic Antibiotics Improve Outcomes in Cirrhotic Patients with GI HemorrhageControl Antibiotic Absolute rate(n=270) (n=264) difference(95% CI)Infection 45% 14% -32%(-42 to –23)SBP / Bacteremia 27% 8% -18%(-26 to –11)Death 24% 15% -9%(-15 to –3)Slide 139PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGEFive randomized controlled trials analyze the effect of prophylactic antibiotics (oral or systemic) in preventing bacterial infections in patients with cirrhosis admitted with gastrointestinal hemorrhage. A meta-analysis of these trials shows that prophylactic antibiotics not only reduce the risk of bacterial infections, including spontaneous bacterial peritonitis and spontaneous bacteremia, but also lead to a significant decrease in mortality. Therefore, the use of antibiotics is considered standard of care in this setting.Bernard B, et al., Hepatology 1999; 29: 1655Meta-analysis of 5 randomized trialsBernard et al., Hepatology 1999; 29:1655
123 PROPHYLACTIC ANTIBIOTICS PREVENT EARLY VARICEAL REBLEEDING Prophylactic Antibiotics Reduce Probability of Recurrent Variceal Hemorrhage1.0Prophylactic antibiotics (n=59)0.8No antibiotics (n=61)0.6%free of variceal hemorrhage0.4Slide 140PROPHYLACTIC ANTIBIOTICS PREVENT EARLY VARICEAL REBLEEDINGIn a randomized controlled trial, patients randomized to prophylactic antibiotics had a significantly lower probability of developing early variceal rebleeding compared to patients who were randomized to on-demand antibiotics (that is, antibiotics given only in the presence of infection).Hou MC, et al., Hepatology 2004; 39: 746Greatest benefit in first 7 days0.212312182430Follow-up (months)Ofloxacin 200 mg iv q12 hr for 2 days, then oral 200 bid for 5 daysHou M-C et al., Hepatology 2004; 39:746
124 Phamacologic Treatment for Acute Variceal Hemorrhage Octreotide:50 microgram bolus and mcg/hr for up to 5 days (range 2-5 days)Vasopressin:Too dangerous for empiric initial therapyContiunuous infusion U/min up to 1.0 U/minRecommended only in combination with i.v. TNG: mcg/minTitrate TNG infusion to maintain systolic BP >90 mmHgContinuous vasopressin> 24 hr not recommended
125 Prophylaxis of HSE in Acute Variceal Bleed 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
126 PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE Endoscopic Therapy Now Standard in the Management of Variceal HemorrhageSlide 139PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGEFive randomized controlled trials analyze the effect of prophylactic antibiotics (oral or systemic) in preventing bacterial infections in patients with cirrhosis admitted with gastrointestinal hemorrhage. A meta-analysis of these trials shows that prophylactic antibiotics not only reduce the risk of bacterial infections, including spontaneous bacterial peritonitis and spontaneous bacteremia, but also lead to a significant decrease in mortality. Therefore, the use of antibiotics is considered standard of care in this setting.Bernard B, et al., Hepatology 1999; 29: 1655
127 Non-Pharmacologic Treatment of Acute Variceal Hemorrhage Endoscopic Band LigationTransjugular Intrahepatic Portal-systemic Shunting (TIPS)Mostly Historical InterestSengstaken-Blakemore TubeEmbolization of varicesPortacaval shunt surgeryInjection Sclerotherapy
128 ENDOSCOPIC VARICEAL BAND LIGATION Bleeding controlled in 90%Rebleeding rate 30%Compared with sclerotherapy:Less rebleedingLower mortalityFewer complicationsFewer treatment sessionsSlide 144ENDOSCOPIC VARICEAL BAND LIGATIONEndoscopic variceal ligation consists of the placement of rubber rings on variceal columns with the objective of interrupting blood flow and subsequently developing necrosis of mucosa and submucosa and replacement of varices by scar tissue. Endoscopic therapy is a local therapy that has no effect on the pathophysiologic mechanisms that lead to portal hypertension and variceal rupture. Even though it achieves variceal obliteration, varices will eventually recur. Bleeding is controlled in 90% of cases of acute variceal hemorrhage with a rebleeding rate of 30%. Meta-analysis of trials comparing ligation with sclerotherapy has shown that ligation is associated with lower rebleeding rates, lower number of sessions to achieve variceal obliteration and lower mortality. Complications of endoscopic therapy are related mainly to the development of esophageal ulceration and strictures, significantly more frequent after sclerotherapy than after ligation.Laine and Cook. Ann Intern Med 1995; 123:280
130 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.)Gastrointest Endosc 2010.
131 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).Gastrointest Endosc 2010.
132 COMBINATION DRUG/ENDOSCOPIC THERAPY IS MORE EFFECTIVE THAN ENDOSCOPIC THERAPY ALONE Combination Drug / Endoscopic Therapy is More Effective Than Endoscopic Therapy Alone in Achieving Five-Day HemostasisSclero + Octreotide Besson, 1995Ligation + Octreotide Sung, 1995Sclero + Octreotide / ST Signorelli, 1996Sclero + Octreotide Ceriani, 1997Sclero + Octreotide Signorelli, 1997Sclero + ST Avgerinos, 1997Sclero + Octreotide Zuberi, 2000Sclero / ligation + Vapreotide Cales, 2001TOTALSlide 143COMBINATION DRUG/ENDOSCOPIC THERAPY IS MORE EFFECTIVE THAN ENDOSCOPIC THERAPY ALONEA meta-analysis of 8 trials comparing endoscopic therapy (sclerotherapy or band ligation) vs. endoscopic therapy + vasoactive drugs (somatostatin, octreotide, vapreotide) shows that combination therapy was better than endoscopic therapy alone in the initial control of bleeding and in achieving 5-day hemostasis. However, there were no differences in survival.Bañares R, et al., Hepatology 2002; 35: 609Relative Risk0.8126.96.36.199.82Favors endoscopic therapy aloneFavors endoscopic plus drug therapyNo Mortality DifferenceBañares R et al., Hepatology 2002; 35:609
133 THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT veinTIPSSlide 147THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNTPortal hypertension can be corrected by creating a communication between the hypertensive portal system and low-pressure systemic veins, bypassing the liver, i.e., the site of increased resistance. This communication can be created surgically or by the transjugular placement of an intrahepatic stent that connects a branch of the portal vein with a branch of an hepatic vein, a procedure designated transjugular intrahepatic porto-systemic shunt (TIPS). TIPS is performed by advancing a catheter introduced through the jugular vein into a hepatic vein and into a main branch of the portal vein. An expandable stent is then introduced connecting hepatic and portal systems, and blood from the hypertensive portal vein and sinusoidal bed is shunted to the hepatic vein. The procedure is highly effective in correcting portal hypertension but can be associated with complications related to diversion of blood flow away from the liver, namely portal-systemic encephalopathy and liver failure.SplenicveinPortal veinSuperior mesenteric vein
134 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)Slide 149TIPS IN THE TREATMENT OF VARICEAL HEMORRHAGEGiven the complications associated to TIPS, its high obstruction rate and its elevated cost, TIPS has been relegated to a secondary position in the treatment of variceal bleeding. In the acute setting, it is used as rescue therapy after failure of two endoscopic therapy sessions. In the chronic setting, it is used in patients whose bleeding recurs despite combination endoscopic/pharmacological therapy. In patients with Child A/B cirrhosis, shunt surgery is an alternative to TIPS.Henderson et al. Hepatology 2004; 40 (Suppl. 1):725A
135 116 cirrhotics with acute variceal bleed Early TIPS In Patients With Acute Variceal Hemorrhage and HVPG > 20 mmHg (High Risk) May Improve Survival116 cirrhotics with acute variceal bleedUrgent assessment of wedged hepatic vein pressure64 HVPG < 20 mmHg: routine therapy52 HVPG > 20 mmHg randomized to TIPS vs routine therapyEarly TIPS in patients with HVPG>20 associated with reduced transfusion, rebleed, in-hospital and 1 year mortalityMonescillo et al., Hepatology 2004; 40:793
136 Probability of survival EARLY TIPS IN PATIENTS WITH ACUTE VARICEAL HEMORRHAGE AND HVPG > 20 mmHg MAY IMPROVE SURVIVALEarly TIPS In Patients With Acute Variceal Hemorrhage and HVPG > 20 mmHg (High Risk) May Improve Survival1HVPG <200.80.6HVPG >20 - TIPSProbability of survival0.4Slide 150EARLY TIPS IN PATIENTS WITH ACUTE VARICEAL HEMORRHAGE AND HVPG > 20 mmHg MAY IMPROVE SURVIVALIn a small randomized study, patients with acute variceal hemorrhage and an HVPG >20 mmHg (predictive of a poor outcome) were randomized to placement of TIPS within 24 hours of the bleeding episode vs. standard therapy. It demonstrates a significantly better survival in patients randomized to TIPS. While these results are interesting and confirm the predictive value of an HVPG >20 mmHg in this setting, this strategy cannot be widely recommended.Monescillo A, et al., Hepatology 2004; 40:793HVPG >20 – No TIPS0.236912MonthsMonescillo et al., Hepatology 2004; 40:793
137 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 therapyRandomized 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 (pharmacotherapy–EBL group, 31 patients).García-Pagán JC et al. N Engl J Med 2010;362:
138 Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding Figure 1. Screening and Randomization of Patients. EBL denotes endoscopic band ligation, and TIPS transjugular intrahepatic portosystemic shunt.García-Pagán JC et al. N Engl J Med 2010;362:
139 Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapy–EBL 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 pharmacotherapy–EBL group versus 97% in the early-TIPS group (P<0.001).Sixteen patients died (12 in the pharmacotherapy–EBL group and 4 in the early-TIPS group, P=0.01).The 1-year actuarial survival was 61% in the pharmacotherapy–EBL group versus 86% in the early-TIPS group (P<0.001)García-Pagán JC et al. N Engl J Med 2010;362:
140 Actuarial Probability of the Primary Composite End Point and of Survival, According to Treatment Group.Figure 2. Actuarial Probability of the Primary Composite End Point and of Survival, According to Treatment Group. The probability of remaining free from uncontrolled variceal bleeding or variceal rebleeding is shown in Panel A, and the probability of survival is shown in Panel B. EBL denotes endoscopic band ligation, and TIPS transjugular intrahepatic portosystemic shunt.No significant differences were observed between the two treatment groups with respect to serious adverse events.García-Pagán JC et al. N Engl J Med 2010;362:
141 Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding
142 MANAGEMENT ALGORITHM IN ACUTE ESOPHAGEAL VARICEAL HEMORRHAGE Management of Acute Variceal HemorrhageMANAGEMENT ALGORITHM IN ACUTE ESOPHAGEAL VARICEAL HEMORRHAGEVariceal Hemorrhage SuspectedInitial ManagementNORescue TIPS/Shunt surgeryBalloon TamponadeYESEarly rebleeding?Acute Hemorrhage Controlled?2nd EndoscopyFurther bleedingProphylaxis against recurrent hemorrhageSlide 158MANAGEMENT ALGORITHM IN ACUTE ESOPHAGEAL VARICEAL HEMORRHAGE
143 Management of Variceal Bleeding Primary ProphylaxisPharmacologicEndoscopicAcute Variceal HemorrhageTIPSSecondary ProphylaxisPharmcologic
144 * HVPG <12 mmHg or >20% from baseline Lowest Rebleeding Rates are Obtained in HVPG Responders and With Ligation + -BlockersLOWEST REBLEEDING RATES ARE OBTAINED IN HVPG RESPONDERS AND IN PATIENTS TREATED WITH VARICEAL BAND LIGATION + BETA-BLOCKERS8060%40Rebleeding20Slide 161LOWEST REBLEEDING RATES ARE OBTAINED IN HVPG RESPONDERS AND IN PATIENTS TREATED WITH VARICEAL BAND LIGATION + BETA-BLOCKERSIn addition to HVPG responders (i.e. patients who achieve a reduction in hepatic venous pressure gradient below 12 mmHg or >20% from baseline) in whom the rebleeding rate is around 10%, two trials comparing the combination of ligation + beta-blockers vs. ligation alone, show that combination therapy is more effective, with rebleeding rates of 14 and 23%, respectively. These therapies are placed in the context of no therapy (red bar) and other less effective therapies (orange bars).Bosch J, and Garcia-Pagan JC, Lancet 2003; 361; 952Lo GH, et al., Hepatology 2000; 32: 461De la Pena J, et al., Hepatology 2005; 41: 572Untreated-blockersSclero-therapy -blockers+ ISMNLigationHVPG-Responders*Ligation+-blockers(19 trials)(26 trials)(54 trials)(6 trials)(18 trials)(6 trials)(2 trials)Bosch and García-Pagán, Lancet 2003; 361:952* HVPG <12 mmHg or >20% from baseline
145 Prophylaxis of Recurrent Variceal Hemorrhage MANAGEMENT ALGORITHM FOR THE PREVENTION OF RECURRENT VARICEAL HEMORRHAGEProphylaxis of Recurrent Variceal HemorrhageControl of Acute Variceal HemorrhageProphylactic Pharmacotherapyand/orEndoscopic Variceal Band LigationRecurrent HemorrhageNOYESSlide 176MANAGEMENT ALGORITHM FOR THE PREVENTION OF RECURRENT VARICEAL HEMORRHAGESurveillance Endoscopyand/orLife-long PharmacotherapyIs patient on EVL + Pharmacotherapy?NOYESInitiate combination RxTIPS/Shunt SurgeryFurther bleeding
146 SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL HEMORRHAGE Evolution of VaricesLevel of InterventionManagement RecommendationsCirrhosis with no varicesRepeat endoscopy in 2-3 yearsNo specific therapyPre-primary prophylaxisSmall varicesNo hemorrhageSmall varicesRepeat endoscopy in 1-2 yearsNo specific therapy? beta-blocker to prevent enlargementMedium/Large varicesNon-selective beta-blockersEVL in those intolerant to drugsMedium / large varicesNo hemorrhagePrimary prophylaxisSlide 180SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL HEMORRHAGEEndoscopic/pharmacologic therapyAntibiotics in all patientsTIPS or shunt surgery as rescue therapyVariceal hemorrhageBeta-blockers + nitrates or EVLBeta-blockers + EVL ?TIPS or shunt surgery as rescue therapySecondary prophylaxisRecurrent variceal hemorrhage
148 Gastric Varices 10-15% of variceal bleeding episodes Limited data from controlled trialsOptimal therapy not knownVasoactive drugs used, but not studiedEndoscopic cyanoacrylate injection:90% control of bleedingBalloon tamponade with Linton-Nachlas tubeTIPS: 90% control of bleedingSlide 182GASTRIC VARICESGastric varices account for 10-15% of variceal bleeding episodes. Because of limited data from controlled trials, optimal therapy is not known. Vasoactive drugs have been used, but not studied. Endoscopic cyanoacrylate obturation of the varices can result in control of up to 90% of patients. A Linton Nachlas tube, which has a gastric balloon of volume 600 mL, may be used for variceal tamponade. TIPS can result in control of bleeding in over 90 percent of patients.
149 CLASSIFICATION OF GASTRIC VARICES GOV 2GOV 1IGV 1Slide 181CLASSIFICATION OF GASTRIC VARICESGastric varices are those that extend from the esophagus into the stomach. They can be subclassified into 2 groups: gastroesophageal varices (GOV, gastric varices that are continuous with esophageal varices) and isolated gastric varices (IGV, gastric varices that occur in the absence of esophageal varices). GOV are in turn classified in GOV1 in which varices extend along the lesser curve for about 2–5 cm below the gastroesophageal junction; and GOV2 which are often long and tortuous and extending from the esophagus below the gastroesophageal junction toward the fundus. IGV are also subclassified into IGV1, varices located in the fundus that often are tortuous and complex in shape; and IGV2, ectopic varices in the antrum, corpus, and around the pylorus. For the purposes of some studies duodenal varices also have been included in this group.IGV 2Sarin et al, Am J Gastro 1989; 84:1244
150 MANAGEMENT ALGORITHM FOR PATIENTS BLEEDING FROM GASTRIC VARICES Management of Acute Gastric (Fundal) Variceal BleedingVariceal Hemorrhage SuspectedTransfuse to hemoglobin ~8 g/dLEarly pharmacotherapyAntibiotic prophylaxisInitial ManagementVariceal obturation possible?NOYESBleeding controlled?Slide 188MANAGEMENT ALGORITHM FOR PATIENTS BLEEDING FROM GASTRIC VARICESIn patients with acute gastric variceal bleeding, initial management consists of transfusion to a hemoglobin of 8 g/dL, pharmacotherapy with vasoactive agents, and antibiotic prophylaxis. Endoscopic treatment is carried out but, if acute hemorrhage is not controlled, TIPS is recommended. If the acute hemorrhage is controlled, and cyanoacrylate is available, obliteration of the gastric varices is attempted with cyanoacrylate. If cyanoacrylate is not available, then TIPS is recommended. A surgical shunt may be considered in patients with Child-Pugh class A cirrhosis.NOYESTIPS*Variceal obliteration +beta-blockersNot possible or rebleed*Surgical shunt may be considered for Child’s Class A
151 MANAGEMENT OF GASTRIC VARICES Gastric varices that are continuous with esophageal varices and extend along the lesser curve (GOV1) should be treated in the same way as esophageal varicesIn patients with isolated fundal varices (IGV1), splenic vein thrombosis should be investigated. If present, treatment consists of splenectomyCirrhotic patients bleeding from gastric fundal varices require specific treatmentSlide 183MANAGEMENT OF GASTRIC VARICESGastric varices that are continuous with esophageal varices and extend along the lesser curvature of the stomach (GOV1) should be treated in the same way outlined for esophageal varices. In patients with isolated fundal varices, particularly in non-cirrhotic patients, the presence of splenic vein thrombosis should be investigated and, if present, treatment consists of splenectomy. Cirrhotic patients bleeding from gastric fundal varices require specific treatment which is different than that outlined for bleeding esophageal varices.
152 ENDOSCOPIC IMAGES OF GASTRIC VARICES Slide 189ENDOSCOPIC IMAGES OF GASTRIC VARICESThe arrow on the panel on the left shows an actively bleeding gastric varix. The panel on the right shows the varix after treatment with cyanoacrylate.Pretreatment cyanoacrylatePost-treatment cyanoacrylate
153 PORTAL HYPERTENSIVE GASTROPATHY Endoscopic changes seen in most patients with portal hypertensionCharacterized by a cobblestone appearance of the mucosa and red signs on endoscopyOften confused with:Gastric Antral Vascular Estasia (GAVE)Watermelon StomachMay be associated with chronic occult bleeding, anemia, and occasionally cause of acute UGI hemorrhageSlide 190PORTAL HYPERTENSIVE GASTROPATHYPortal hypertensive gastropathy (PHG) is characterized endoscopically by a mosaic pattern with red signs. Changes can also be seen in the small intestine and colon, especially the right colon. PHG is a cause of chronic blood loss in cirrhotic patients, but can be a source of acute bleeding.
154 SEVERE PORTAL HYPERTENSIVE GASTROPATHY MAY BE DIFFICULT TO DISTINGUISH FROM DIFFUSE GAVE Slide 201SEVERE PORTAL HYPERTENSIVE GASTROPATHY MAY BE DIFFICULT TO DISTINGUISH FROM DIFFUSE GAVEThis slide shows the difference between severe portal hypertensive gastropathy (left panel) and diffuse gastric antral vascular ectasia (GAVE, right panel). Note the mosaic pattern with severe PHG, but absence of a mosaic pattern in GAVE.Severe PHGDiffuse GAVE
155 ENDOSCOPIC IMAGES OF THE TWO TYPES OF GASTRIC ANTRAL VASCULAR ECTASIA Slide 200ENDOSCOPIC IMAGES OF THE TWO TYPES OF GASTRIC ANTRAL VASCULAR ECTASIAThe panel on the left shows a typical watermelon stomach with linear aggregates of red signs without a background mosaic pattern. The panel on the right shows a diffuse variety of vascular ectasia with red signs in the absence of a background mosaic pattern.Typical GAVE “watermelon stomach”Diffuse GAVE
156 GASTRIC ANTRAL VASCULAR ECTASIA Gastric Antral Vascular Ectasia (GAVE)Endoscopic findings:Red spots without background mosaic patternLinear aggregates in antrum: “watermelon stomach”Diffuse lesions in proximal and distal stomachMay be difficult to differentiate from portal hypertensive gastropathy (PHG)Ideal therapy not knownSlide 198GASTRIC ANTRAL VASCULAR ECTASIAGastric antral vascular ectasia (GAVE) is less commonly seen than portal hypertensive gastropathy. It is characterized by red spots without a background mosaic pattern. The lesions are typically in the antrum. If there are aggregates in the antrum with a linear distribution, the term “watermelon stomach” is used. Lesions can be more diffuse and can also be seen in the proximal stomach. GAVE may occur in the absence of portal hypertension, is difficult to differentiate from PHG, and ideal therapy is not known.
159 VARICEAL WALL TENSION IS A MAJOR DETERMINANT OF VARICEAL RUPTURE Variceal Wall Tension (T) is a Major Determinant of Variceal RuptureEsophagusWall thickness (w)Radius (r)Transmural pressure (tp)VarixSlide 99VARICEAL WALL TENSION IS A MAJOR DETERMINANT OF VARICEAL RUPTURERupture of a vessel occurs when the expanding force exceeds its maximal wall tension. The higher the tension, the greater the possibility of rupture. Tension in the varix (T) is directly proportional to transmural pressure (difference between the intravariceal and the intraluminal esophageal pressure) and to variceal radius (r) and is inversely proportional to variceal wall thickness. A large varix has a large radius and a thin wall and therefore a larger tension and a greater propensity to rupture.Groszmann RJ. Gastroenterology 1984; 80:1611Tension (T)T = tp xrwGroszmann, Gastroenterology 1984; 80:1611
160 MANAGEMENT OF PATIENTS WITHOUT VARICES Treatment of Varices / Variceal HemorrhagePrevent Formation of Varices ?No varicesVaricesNo hemorrhagePrevent First Variceal HemorrhageControl Bleeding: Reduce MortalityVaricealhemorrhageSlide 112MANAGEMENT OF PATIENTS WITHOUT VARICESIn cirrhotic patients who have not yet developed varices, no specific therapy is recommended. However, a surveillance endoscopy should be performed every 2-3 years in compensated cirrhosis and annually in decompensated cirrhosis.Prevent Recurrent HemorrhageRecurrenthemorrhage
161 Endoscopic Findings Which is the best option? Start atenolol Start propranololVariceal band ligationPropranol and isosorbide mononitrateBand ligation and beta blockers
162 Bleeding controlled with band ligation, antibiotics an octreotide No bleeding for 5 daysChild score 10. MELD 15 MAP 90 mmHgWhich is the best discharge regiment?1) Beta blockers and nitrates2) Serial ligation alone3) Ligation and beta blockers4) TIPS5) Portacaval shunt
163 Prevention of Recurrent Bleeding TIPS vs. Drug Therapy 91 Childs-Pugh class B/C cirrhotic patients who survived first variceal hemorrhageRandomized to TIPS(47) vs propranolol plus isosorbide-5-mononitrate(44)Followed for 2 yearsAssess hepatic encephalopathy, recurrent variceal hemorrhage, costs, number of medical interventions, and survivalHepatology 2002;35:385-92