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Prevention and Management of Esophageal Variceal and Portal Hypertensive Hemorrhage

Prevention and Management of Esophageal Variceal and Portal Hypertensive Hemorrhage. Thomas Hargrave, M.D. March 24, 2012. Gastroesophageal Variceal Hemorrhage. Gastroesophageal variceal hemorrhage is one of the major complications of portal hypertension from cirrhosis

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Prevention and Management of Esophageal Variceal and Portal Hypertensive Hemorrhage

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  1. Prevention and Management of Esophageal Variceal and Portal Hypertensive Hemorrhage Thomas Hargrave, M.D. March 24, 2012

  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

  3. PREVALENCE AND SIZE OF ESOPHAGEAL VARICES IN PATIENTS WITH NEWLY DIAGNOSED CIRRHOSIS Prevalence and Size of Esophageal Varices in Patients with Newly-Diagnosed Cirrhosis 100 80 Large % Patients with varices 60 Medium 40 20 Small 0 Child C n=34 Overall n=494 Child A n=346 Child B n=114 Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72

  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%.

  5. Portal Venous Anatomy Pathophysiology

  6. 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

  7. Hepatic Lobular Anatomy

  8. 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.

  9. Intracellular Spaces (of Disse) in the Portal Sinusoids Large Enough for Chylomicroms to Pass

  10. Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:823-832.

  11. 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 Form Varices Present (n=72) Varices Absent (n=15) 35 30 Hepatic Venous Pressure Gradient (mmHg) 25 20 P<0.01 15 12 10 5 Garcia-Tsao et. al., Hepatology 1985; 5:419

  12. Venous Layers of the Esophagus

  13. VARICES INCREASE IN DIAMETER PROGRESSIVELY Varices Increase in Diameter Progressively No varices Small varices Large varices 7-8%/year 7-8%/year Merli et al. J Hepatol 2003;38:266

  14. Grade II Varices Grade III Varices

  15. LARGE VARICES ARE MORE LIKELY TO RUPTURE Large Varices Are More Likely To Rupture No Varices 100 p<0.01 * Small Varices 75 % Patients without bleeding Large Varices ** 50 • 2-year probability of first bleed: • Small varices: 7% • Large varices: 30% 25 0 36 12 36 24 0 12 24 Time (months) *Merli et al., Hepatol 2003; 38:266, **Conn et al., Hepatology 1991; 13:902

  16. Punctum Variceal hemorrhage Varix with red wale sign

  17. Management of Variceal Bleeding • Primary Prophylaxis • Pharmacologic • Endoscopic • Acute Variceal Hemorrhage • Pharmacologic • Endoscopic • TIPS • Secondary Prophylaxis • Pharmcologic • Endoscopic • TIPS

  18. Primary Prophylaxis In 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.

  19. MANAGEMENT OF PATIENTS WITHOUT VARICES Can we prevent formation of varices ? Treatment of Varices / Variceal Hemorrhage No varices Varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage

  20. 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 patients • Beta-blockers did not prevent the development of varices and were associated with a higher rate of serious adverse events • In patients without varices, treatment with nonselective beta-blockers is not recommended Groszmann, et al., Hepatology 2003;38 (suppl 1):206A

  21. MANAGEMENT OF PATIENTS WITHOUT VARICES No specific therapy Repeat endoscopy in 2-3 yrs* Treatment of Varices / Variceal Hemorrhage No varices Varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage * Sooner with cirrhosis decompensation

  22. PREVENTION OF FIRST VARICEAL HEMORRHAGE Treatment of Varices / Variceal Hemorrhage No varices Prevention of first variceal hemorrhage Varices No hemorrhage Variceal hemorrhage Recurrent hemorrhage

  23. Primary Prophylaxis for Variceal Hemorrhage • Pharmacologic Therapy • Beta Blockers • Nitrates • Endoscopic Therapies • Band Ligation • Sclerotherapy (historican interest only)

  24. DECREASE IN HEPATIC VENOUS PRESSURE GRADIENT (HVPG) REDUCES THE RISK OF VARICEAL BLEEDING Decrease In Hepatic Venous Pressure Gradient (HVPG) Reduces Risk of Variceal Bleeding 100 80 46-65% 60 % Rebleeding 40 7-13% 20 0% 0 HVPG decrease to < 12 mmHg HVPG decrease > 20% from baseline No change in HVPG Bosch and García-Pagán, Lancet 2003; 361:952

  25. 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

  26. NON-SELECTIVE BETA-BLOCKERS PREVENT FIRST VARICEAL HEMORRHAGE Non-Selective Beta-Blockers Prevent First Variceal Hemorrhage: 11 Trials Bleeding rate Control Beta-blocker Absolute rate (~2 year) difference All 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) D’Amico et al., Sem Liv Dis 1999; 19:475

  27. Primary Prophylaxis against Variceal Hemorrhage. Garcia-Tsao G, Bosch J. N Engl J Med 2010;362:823-832.

  28. THE RISK OF FIRST VARICEAL HEMORRHAGE IS NOT REDUCED BY ADDING ISOSORBIDE MONONITRATE (ISMN) TO BETA-BLOCKERS Propranolol + ISMN Propranolol + ISMN Propranolol + placebo Propranolol + placebo The Risk of First Bleeding is Not Reduced by Adding Isosorbide Mononitrate (ISMN) to b-blockers Free of a first variceal bleeding Survival 100 100 ns ns 75 75 % 50 50 25 25 0 0 1 2 1 2 Years Years García-Pagán et al., Hepatology 2003; 37:1260

  29. ENDOSCOPIC VARICEAL BAND LIGATION Endoscopic Variceal Band Ligation

  30. 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.

  31. VARICEAL BAND LIGATION (VBL) VS. BETA-BLOCKERS (BB) IN THE PREVENTION OF FIRST VARICEAL HEMORRHAGE First hemorrhage Survival Chen 1998 Sarin 1999 De 1999 Jutabha 2000 De la Mora 2000 Lui 2002 Lo 2004 Schepke 2004 Total Relative risk 0 1 0 1 10 10 40 Favors BB Favors BB Favors VBL Favors VBL Variceal Band Ligation (VBL) vs. Beta-Blockers (BB) in the Prevention of First Variceal Bleed Khuroo, et al., Aliment Pharmacol Ther 2005; 21:347

  32. MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARY Diagnosis of Cirrhosis Endoscopy No Varices Medium/Large Varices Child’s C or Stigmata Small Varices Follow-up EGD in 2-3 years* Follow-up EGD in 1-2 years* *EGD every year in decompensated cirrhosis Beta-blocker therapy No Contraindications • Stepwise increase until maximally tolerated dose • Continue beta-blocker (life-long) • No role for repeated endoscopy!! Contraindications or Beta-blocker intolerance Endoscopic Variceal Band Ligation Prophylaxis of Variceal Hemorrhage No role for sclerotherapy or nitrates

  33. 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) Hepatology 2001; 34(6):1096-02

  34. Management of Variceal Bleeding • Primary Prophylaxis • Pharmacologic • Endoscopic • Acute Variceal Hemorrhage • Pharmacologic • Endoscopic • TIPS • Secondary Prophylaxis • Pharmcologic • Endoscopic • TIPS

  35. TREATMENT OF ACUTE VARICEAL HEMORRHAGE 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

  36. 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<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 group Colomo A. et al , Abstract 232A (AASLD 2008)

  37. Cautious Transfusion Improves Outcome in Cirrhotics with Variceal Hemorrhage P= 0.02 P= 0.04 6-week survival in variceal bleeders who did not have therapeutic failure Colomo A. et al , Abstract 232A (AASLD 2008)

  38. Prophylactic Antibiotics Improve Outcomes in Cirrhotic Patients with GI Hemorrhage 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 IV Scand J. Gastro 2003;38:193-200

  39. PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE Prophylactic Antibiotics Improve Outcomes in Cirrhotic Patients with GI Hemorrhage Control 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) Meta-analysis of 5 randomized trials Bernard et al., Hepatology 1999; 29:1655

  40. PROPHYLACTIC ANTIBIOTICS PREVENT EARLY VARICEAL REBLEEDING Prophylactic Antibiotics Reduce Probability of Recurrent Variceal Hemorrhage 1.0 Prophylactic antibiotics (n=59) 0.8 No antibiotics (n=61) 0.6 % free of variceal hemorrhage 0.4 Greatest benefit in first 7 days 0.2 0 24 3 30 18 12 0 2 1 Follow-up (months) Ofloxacin 200 mg iv q12 hr for 2 days, then oral 200 bid for 5 days Hou M-C et al., Hepatology 2004; 39:746

  41. 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

  42. 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

  43. PROPHYLACTIC ANTIBIOTICS IMPROVE OUTCOMES IN CIRRHOTIC PATIENTS WITH GI HEMORRHAGE Endoscopic Therapy Now Standard in the Management of Variceal Hemorrhage

  44. 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

  45. ENDOSCOPIC VARICEAL BAND LIGATION Endoscopic Variceal Band Ligation • Bleeding controlled in 90% • Rebleeding rate 30% • Compared with sclerotherapy: • Less rebleeding • Lower mortality • Fewer complications • Fewer treatment sessions

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