Management of Adult Patients With Ascites Due to Cirrhosis AASLD 2004 Guideline Ahmed Mayet, Pharm.D. Liver Blood Supply. 75% blood supply by portal and hepatic veins 25% by hepatic arteries. Hepatocytes function as detoxification of toxic substances and synthesizer of proteins,
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Management of Adult Patients With Ascites Due to CirrhosisAASLD 2004 GuidelineAhmed Mayet, Pharm.D
Liver Blood Supply • 75% blood supply by portal and hepatic veins • 25% by hepatic arteries
Hepatocytes function as detoxification of toxic substances and synthesizer of proteins, carbohydrates, hormones and related materials Kupffer Cell act as phagocytic cell
Pre-Hepatic Sinusoidal Pre-Sinusoidal Post- Sinusoidal Classification Post- Hepatic
Definition: • Cirrhosis of the liver is the result of various disease processes and is characterized by diffuse fibrosis and conversion of the normal liver architecture into structurally abnormal nodules.
Definitions Fibrosis • Excess deposition of the components of extracellular matrix (collagens, glycoproteins, proteoglycans) within the liver • Reversible process Cirrhosis • Diffuse hepatic process characterized by fibrosis and conversion of normal liver architecture into structurally abnormal nodules • Irreversible process
Most common causes Hepatitis (26%) Alcoholic liver disease (21%) Hepatitis C+ alcoholic disease (15%) Cryptogenic causes(18%) Hepatitis B(15%) Miscellaneous (5%) Miscellaneous (5%) Autoimmune hepatitis Primary billiary cirrhosis Secondary billiary cirrhosis Primary sclerosing cholangitis Hemochromatosis Wilson disease Alpha-1 antitrypsin deficiency Drug induced Venous outflow obstruction (budd-chiari syndrome) Chronic right side heart failure Etiology
Sign and Symptoms and clinical finding of Liver Cirrhosis • Anorexia, nausea, abdominal discomfort, weight loss, and malaise • Ascites, peripheral edema, jaundice, spider nevi, palmar erythema • Gynecomastia, testicle atrophy, amenorrhea, pubical hair lost • Hepatomegaly, spleenomegaly, encephalopathy, and bleeding
Laboratory Findings • Initially elevated ALT and AST level but at the end stage they can be normal or below normal • Elevated bilrubin most of the time • Low albumin level • Prolong prothrombin time (PT) and APTT • Elevated serum creatinine and blood urea nitrogen (BUN)
Classification Based on total points, a patient with cirrhosis is assigned to one of three classes: Child class A = 5 to 6 points; Child class B = 7 to 9 points; Child class C = 10 to 15 points. Gastroenterology 2001;120:727
Complications • Portal hypertension • Variceal Hemorrhage • Ascites • Spontaneous Bacterial Peritonitis • Hepatic Encephalopathy • Hepatorenal Syndrome
Risks of Complications of Cirrhosis ?30+% HCC Death 1.5% 11% 2.5% Ascites Cirrhosis ?20+% 1.1% Variceal Bleeding 0.4% Liver Transplant percent per year Encephalopathy Bennett WG et al, Ann Intern Med 1997;127:855
Portal Hypertension • Portal pressure increases to 5 mmHg more than the pressure in the inferior vena cava • Development of varices and alternative routes of blood flow • Risk of varices when portal pressure exceed the vena cava pressure by > 12 mmHg • Hemorrhage from varices occurs in 25-40% of cirrhotic patients • Each episode of bleeding carries a 30% risk of death
Target for Therapy Cirrhosis Splanchnic arteriolar resistance Resistance to portal flow Venodilators Portal Pressure Portal blood flow Varices/Variceal Hemorrhage
Prevention of First Variceal Hemorrhage Non-selective Beta-blockers prevent first variceal hemorrhage: D’Amico et al, Sem Liv Dis. 1999
Treatment of Varices/Variceal Hemorrhage Varices No hemorrhage Small Varices No hemorrhage Prevention of variceal growth? Medium/large varices No hemorrhage
Preventing Growth of Small Varices Nadolol may prevent the growth of small varices: Merkel et al, Gastroentrology 2004
Treatment of Varices/Variceal Hemorrhage Varices No hemorrhage • Beta-Blockers (propranolol or nadolol) indefinitely • Endoscopic variceal ligation in patients intolerant or contraindicated to beta-blockers Small Varices No hemorrhage Medium/large varices No hemorrhage
ESOPHAGEAL VARICEAL BLEEDING • Primary prophylaxis • Pharmacotherapy: • Non selective β-Blocker (Propranolol) • ↓Portal pressure by ↓CO → ↓ Blood flow. • Long acting BB (Nadolol) or propanolol • Average dose of (60 mg/d), preferred in the evening, mean dose 160 mg/d • HR not less than 55 beats/min & SBP not less than 90 mm Hg. • Adverse effects in 27% of patients. • What are they?
Target for Therapy Cirrhosis Splanchnic arteriolar resistance Resistance to portal flow Portal Pressure Variceal band ligation/ sclerotherapy Portal blood flow Variceal Obliteration
Endoscopic varicieal band ligation Endoscopic varicieal band ligation: Bleeding controlled in 90% Rebleeding rate 30% Compared with sclerotherapy: Less rebleeding Less mortality Fewer complications Fewer treatment sessions Laine and Cook. Ann Intern Med 1995
Prevention of First Variceal Hemorrhage Variceal Band Ligation (VBL) vs. beta-blockers: Khuroo et al, Aliment Pharmacol Ther 2005
ESOPHAGEAL VARICEAL BLEEDING, Cont’d • Endoscopic therapy: • Endoscopic variceal sclerotherapy is not recommended in the primary prophylaxis of variceal bleeding. • Endoscopic variceal band ligation (EVL) was shown to be safe and more effective than propranolol in the primary prophylaxis of variceal bleeding. • Further confirmation is needed.
Prophylaxis of Variceal Hemorrhage Diagnosis of Cirrhosis Endoscopy No varives Small varives Medium/large varives Follow-up endoscopy in 2-3 years Beta-blocker therapy No CI • Stepwise increase until maximum tolerated dose • Continue beta-blockers life-long CI or intolerance Endoscopic variceal band ligation
Treatment of Varices/Variceal Hemorrhage No Varices Varices No hemorrhage Variceal hemorrhage Control hemorrhage Recurrent hemorrhage
Treatment of Acute Variceal Hemorrhage General management: IV access & fluid resuscitation Do not over transfuse (Hgb about 8) Fresh frozen plasma, Vit K Antibiotic prophylaxis Specific therapy: Pharmacological therapy terlipressin, somatostatin, Octreotide, vasopressin + NG Endoscopic therapy (ligation or sclerotherapy) Shunt therapy: TIPS or surgical shunt
Acute variceal Bleeding, Cont’d • Pharmacotherapy: • While a waiting for endoscopy • Give Vasopressin: 0.2-0.9 IU/min IV infusion for maximum of 24 to 48 hours • Associated with major complications such as angina, arrhythmia, MI, bowel, liver and spleen infarction and local tissue necrosis and CVA • No longer recommended • The combination of vasopressin with nitroglycerin more effective & reduced the cardiac complications.
Acute variceal Bleeding, Cont’d • Pharmacotherapy, Cont’d • Terlipressin: • Analogue of vasopressin. • Has a longer half-life than vasopressin and can be given as a bolus infusion q4h. • As effective as vasopressin with less SE. • Dose: 2 mg IV 6 hourly till bleeding stops and then 1 mg IV 6 hourly for further 24 hours.
Acute variceal Bleeding, Cont’d • Pharmacotherapy, Cont’d • Octreotide: • A synthetic analogue of somatostatin. • Widely used to control acute variceal hemorrhage • Has been shown to be effective in controlling bleeding and in decreasing bleeding related mortality. • Bolus dose of 50 mcg and continuous IV infusion of 50 mcg/h for 5 days.
Pharmacological TreatmentOctreotide Dosing Recommendations: Given initially as a 50-mg intravenous bolus then as a constant infusion at 50 mg/h for 3 to 5 days Main Side Effects: Dizziness, fatigue, headache, diarrhea, abdominal pain, bradycardia, dysrhythmias, blurred vision & nausea
Acute variceal Bleeding, Cont’d • Endoscopic Therapy • Endoscopic injection of hypertonic solution (sclerotherapy) controls active hemorrhage from esophageal varices in about 90% of patients. • Endoscopic variceal band ligation (EVL) was shown to be comparable to endoscopic sclerotherapy with less complications. • EVL is currently the initial procedure of choice. • Complications of EVL include • Superfacial ulceration and dysphagia • Transient chest discomfort and rarely esophageal strictures
Acute variceal Bleeding, Cont’d • Other modalities • Balloon tamponade • Cold ice water lavage • Surgery • Transjugular intrahepatic portosystemic shunt (TIPS)
Treatment of Acute Variceal Hemorrhage Prophylaxis antibiotics improves outcome in cirrhotic patients with GI hemorrhage: Bernard B, et al. hepatology 1999
Treatment of Acute Variceal Hemorrhage Probability of remaining free of recurrent variceal hemorrhage: Hou MC, et al. hepatology 2004
Treatment of Acute Variceal Hemorrhage Vasoactive drugs are as effective as sclerotherapy in acute variceal hemorrhage: D’Amico G, et al. gastroentrology 2003
Treatment of Acute Variceal Hemorrhage Combination of pharmacological therapy/endoscopic therapy is more effective than endoscopy alone: Banares R et al. hepatology 2002
Treatment of Acute Variceal Hemorrhage Endoscopic varicieal band ligation: Bleeding controlled in 90% Rebleeding rate 30% Compared with sclerotherapy: Less rebleeding Less mortality Fewer complications Fewer treatment sessions Laine and Cook. Ann Intern Med 1995
Treatment of Acute Variceal Hemorrhage Transjugular intrahepatic portsystemic shunt (TIPS)
Treatment of Acute Variceal Hemorrhage Transjugular intrahepatic portsystemic shunt (TIPS): TIPS in rescue therapy for recurrent variceal hemorrhage: (at second rebreeding for esophageal varices) TIPS is indicated in patients who rebleed on combination endoscopic plus pharmacological therapy In patients with Child A/B cirrhosis, the distal spleno-renal shunt is as effective as TIPS Henderson et al. Hepatology 2004
Treatment of Varices/Variceal Hemorrhage No Varices Varices No hemorrhage • Safe vasoactive drug + endoscopic therapy + antibiotic therapy • TIPS/shunt (rescue therapy) Variceal hemorrhage Recurrent hemorrhage
Treatment of Varices/Variceal Hemorrhage No Varices Varices No hemorrhage Variceal hemorrhage Preventing recurrent hemorrhage Recurrent hemorrhage
Secondary Prophylaxis Lowest rebleeding rates are obtained in HVPG responders & with ligation + beta-blockers: Bosch J, and Garcia-Pagan JC, Lancet 2003. Lo GH, et al. hepatology 2000. De la pena J, et al. hepatology 2005
Pharmacological TreatmentBeta-Blockers Dosing Recommendations: The most commonly used is propranolol & nadolol The initial dose of nadolol is between 40-80 mg & propranolol is 20-40 given at bedtime and titrated every 4 to 5 days to reduce heart rate by 25% from baseline or to a heart rate of 55 beats per minute