Subject Review. Pathophysiology and Treatment of Variceal Hemorrhage M.D., AND PATRICK S. KAMATH, M.D.

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1 Subject Review Pathophysiology and Treatment of Variceal Hemorrhage LEWIS R. ROBERTS, M.D., AND PATRICK S. KAMATH, M.D. Portal hypertension results from increases in portal flow and portal vascular resistance. Factors increasing portal blood flow are predominantly humoral. Resistance to portal flow has a fixed component due to distortion of the vasculature by cirrhotic nodules and a variable component that is related to vasoactive substances. Varices result from an increase in portal pressure. Factors predicting the risk of variceal bleeding include continued alcohol use, poor liver function, large varices, and red wale markings on varices at endoscopy. Octreotide is probably the drug of choice for pharmacologic management of bleeding esophageal varices. Propranolol has an established role in the prevention of variceal hemorrhage, and The three major and potentially fatal complications of cirrhosis of the liver-namely, variceal hemorrhage, ascites, and encephalopathy-are related to portal hypertension, which is defined as a hepatic venous pressure gradient (HVPG) of greater than 6 mm Hg. The elevation of portal pressure in cirrhosis results from increased resistance to flow of portal venous blood at the presinusoidal, sinusoidal, or postsinusoidallevel. With increasing portal pressure, a portosystemic collateral circulation develops, the consequences of which include variceal hemorrhage, ascites, and portosystemic encephalopathy. Herein we review the pathophysiology of portal hypertension in patients with cirrhosis of the liver and discuss, in particular, the management of the major consequence of portal hypertension-variceal hemorrhage. PATHOGENESIS OF PORTAL HYPERTENSION As in all vascular systems, pressure within the portal system is a product of flow and resistance; thus, portal pressure equals portal flow X resistance to portal flow. Increases in portal flow, resistance, or both result in increased portal venous pressure. 1 Cirrhosis of the liver is characterized by systemic and splanchnic vasodilatation. This increased state causes a hyperdynamic circulation with a high cardiac outfrom the Division of Gastroenterology and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. P. S. Kamath, Division of Gaslroenterology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN Mayo Clin Proc 1996; 71: variceal band ligation may be the preferred endoscopic technique. Transjugular intrahepatic portosystemic shunts have emerged as an important treatment for patients in whom pharmacologic and endoscopic therapies have failed and are an effective bridge to liver transplantation. (Mayo Clin Proc 1996; 71: ) ET } = endothelin-l; EVL = endoscopic variceal ligation; ~HVP =free hepatic venous pressure; HVPG =hepatic venous pressure gradient; SBP = spontaneous bacterial peritonitis; TIPS = transjugular intrahepatic portosystemic shunts; TNF-a = tumor necrosis factor; WHVP = wedged hepatic venous pressure put, tachycardia, and relative hypotension in the systemic circulation and increased mesenteric and portal blood flow in the splanchnic circulation. This state of vasodilatation has been recognized for more than 40 years.' The factors believed to be responsible for the vasodilatation include nitric oxide.v' In contrast, resistance to portal flow is related both to mechanical factors distorting the liver microcirculation and to vasoactive substances modulating flow through the liver. Factors That Increase Portal Blood Flow.-Systemic vasodilatation has been demonstrated in animal models of both prehepatic portal hypertension (portal vein-ligated rats) and intrahepatic portal hypertension (rats with cirrhosis of the liver induced by carbon tetrachloridej.v' In these animals, there is hyporesponsiveness of the mesenteric arterial bed to vasoconstrictors such as norepinephrine? and endothelin," which results in vasodilatation and thus increased mesenteric and portal blood flow. This decreased responsiveness to vasoconstrictors seems to be due to the presence of vasodilatory substances, including prostaglandins," glucagon,'" and nitric oxide.v Glucagon, the most studied of these substances, accounts for only 30 to 40% of the splanchnic vasodilatation of chronic portal hypertension Recent evidence indicates that arterial hypotension in cirrhotic rats with ascites may be induced by nitric oxide because nitric oxide inhibitors correct arterial hypotension." Tumor necrosis factor (TNF-a) has also been implicated in the vasodilatation of prehepatic portal hypertension. In an Mayo Foundation/or Medical Education and Research

2 974 animal model of portal hypertension produced by ligation of the portal vein, anti-tnf-a. increased arterial pressure, heart rate, and systemic vascular resistance." The hyperdynamic circulation was almost completely abolished by inhibition of TNF-a.. Thus, current evidence points to glucagon, prostaglandins, nitric oxide, and, probably, TNF-a. as the candidate substances involved in the vasodilatation of cirrhosis of the liver (Table 1). These vasodilator substances are probably splanchnic in origin and accumulate in the systemic circulation because of either increased production or decreased metabolism by the diseased liver. With progression of liver disease, portosystemic shunting occurs, which further decreases hepatic uptake and increases levels of vasodilator substances in the systemic circulation. Hence, vasodilators may be important not only in the initiation of portal hypertension but also in its propagation. Factors That Increase Resistance to Portal Flow.-The major site of resistance within the portal circulation is at the level of the sinusoids. Resistance to blood flow has two components-a fixed component, which is related to distortion of the vessels by cirrhotic nodules, and a variable component, which is related to vasoactive substances (Table 1). The reversible factors that mediate vascular resistance have not been as well studied as the factors that increase portal blood flow. Several years ago, Bhathal and Grossman" demonstrated that resistance to blood flow within the liver could be modified by vasoactive substances. Our studies in bile duct-ligated rats suggest that the reversible component of intrahepatic resistance may be modulated by endothelins and that nitric oxide has less of a role. Endothelins are a family of vasoactive peptides, of which endothelin-i (ET-1) is a potent constrictor of vascular smooth muscle. ET-1 is increased in the peripheral blood of patients with chronic liver disease and ascites" and in those with the hepatorenal syndrome." ET-1 has been localized to the endothelial cells of the hepatic sinusoids, portal vein, and central vein. I? In a rat model, an endothelin blocker decreased intrahepatic resistance toward normal, whereas in control animals, no change was noted. IS This finding suggests that endothelin is at least partly responsible for the increased resistance to portal blood flow in cirrhosis of the liver. The mechanisms underlying this phenomenon must be explored further. MEASUREMENT OF PORTAL PRESSURE Portal pressure can be measured in several ways, the most common of which is measurement of wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP) with use of a femoral vein approach. The procedure aims at measuring pressure within the hepatic sinusoids. The most reproducible method for measuring WHVP is by using a Mayo Clin Proc, October 1996,Vol71 Table I.-Pathophysiology of Portal Hypertension Factors increasing portal blood flow Nitric oxide Glucagon Prostaglandins Tumor necrosis factor a Factors increasing resistance to portal blood flow Fixed component Fibrosis Vascular distortion by nodules Variable component? Endothelin balloon catheter. When the catheter is in the wedged position, the pressure tracing is stable, with no reflux of contrast into the portal vein; withdrawal of the catheter results in a precipitous decrease in pressure.'? FHVP is measured at the junction of the hepatic vein and the inferior vena cava. WHVP represents hepatic sinusoidal pressure, somewhat akin to pulmonary wedge pressure representing left atrial pressure. The FHVP is the reference for measurement of portal pressure, similar to right atrial pressure being the reference for systemic venous pressure. The difference between WHVP and FHVP is the HVPG, and in normal subjects, it is less than 5 mm Hg. Portal hypertension is diagnosed when the HVPG is greater than 6 mm Hg. The risk of variceal bleeding increases when the HVPG is higher than 12 mm Hg and is insignificant when the HVPG is lower than this level." WHVP best represents sinusoidal pressure in alcoholic liver disease and posthepatic cirrhosis. In cholestatic liver diseases like primary biliary cirrhosis, WHVP is somewhat less than the portal pressure, an indication of a presinusoidal component of portal resistance. Similarly, WHVP underrepresents sinusoidal pressure in venoocclusive disease and is normal in portal venous thrombosis causing portal hypertension. Normal liver hemodynamic values are listed in Table 2. Two other measurements deserve comment-namely, esophageal variceal pressure and azygos blood flow. The risk of a variceal hemorrhage is related to pressure within the varix. Attempts have been made to measure pressure within the varix at endoscopy by using either a needle or a balloon; the balloon technique is safer." Measurement of variceal pressure has not been studied extensively enough to determine the pressure level below which variceal hemorrhage is not likely to occur. Azygos blood flow (Fig. 1) is measured by a thermal dilution technique. Most of the portosystemic collateral blood flow is returned to the superior vena cava through the azygos vein, and thus azygos blood flow is a good representation of the amount of collateral circulation. In normal subjects, azygos blood flow is less than 200 mli min, whereas in patients with portal hypertension, it is in-

3 Mayo Clio Proc, October 1996, Vol 71 Table 2.-Normal Liver Hemodynamic Values Measurement Pressures (mm Hg) Hepatic artery Portal vein Inferior vena cava Wedged hepatic venous pressure (WHVP) Free hepatic venous pressure (FHVP) Hepatic venous pressure gradient (WHVP-FHVP) Flow rates and volumes (ml/min) Estimated hepatic blood flow Hepatic artery blood flow Portal blood flow Hepatic blood volume (ml) Oxygen supply to the liver (%) Through portal vein Through hepatic artery Normal value <6 1, , Modified from Kamath PS. Haemodynamics of the liver and its alteration in disease. Trop Gastroenterol 1983; 4: creased to 220 to 1,600 mlzmin." Measurement of azygos blood flow is not helpful in the routine clinical management of variceal hemorrhage, but it is a useful research tool CONSEQUENCES OF INCREASED PORTAL PRESSURE Variceal hemorrhage, ascites, and portosystemic encephalopathy are the major consequences of portal hypertension. This discussion focuses on the pathogenesis of variceal formation. Normal resistance to portal blood flow is at the level of the hepatic sinusoid. The classification of portal hypertension based on the site of obstruction is depicted in Figure 2. Portosystemic collateral vessels have a high resistance, and thus splanchnic blood normally flows almost entirely into the portal vein. With increased blood flow to the liver due to splanchnic vasodilatation, resistance to blood flow within the portal venous system increases, an outcome that results in the opening of portosystemic collateral channels. Splanchnic blood can now flow either into the portal vein or through the collateral veins. With increasing resistance to blood flow in the portal circulation due to both humoral and mechanical factors, portal flow decreases, and collateral blood flow increases. The collaterals are formed at sites where systemic veins are close to veins that normally drain into the portal system. These collaterals manifest as varicosities at the lower end of the esophagus between the left gastric vein and the azygos vein; in the rectum, between the inferior hemorrhoidal plexus and the middle and superior hemorrhoidal plexus; around the umbilicus; and around the ovaries. Varices also develop at other sites including the small bowel, cecum, and stomal sites, and these are referred 975 to as ectopic varices. The risk of bleeding from varices is minimal when the HVPG is lower than 12 mm Hg. A recent study showed that portal pressure has a circadian variation, in which HVPG is highest shortly after midnight, decreased significantly after 9 AM, and lowest at 7 PM. 23 This circadian variation might explain why variceal hemorrhage occurs more often during the early hours that at any other time during the day." DETECTION OF VARICES When esophageal varices are noted, portal pressure is invariably high, although no clear correlation exists between the development of varices and the degree of portal hypertension." The most common method of detecting varices is by endoscopy. Transcutaneous ultrasonography demonstrates varices in a large percentage of patients, but its major role is in determining patency of the portal venous system." Computed tomography and magnetic resonance angiography can also detect varices. Although no studies have compared these radiologic techniques to endoscopy, they are generally considered inferior for the detection of varices. Angiography is useful for delineation of the portal venous system. The usual technique used for this purpose is venous phase celiac artery angiography. Angiography can also detect fistulas between the arterial system and the portal venous system. The fistula can be between the splenic artery and the splenic vein, but it is usually between a branch of the hepatic artery and the portal vein and may be a consequence of a liver biopsy. Angiography demonstrates not only the venous collaterals but also the site of the fistula. Contrast angiography is essential before a portosystemic shunt surgical procedure is planned because Doppler ultrasonography and magnetic resonance imaging may not always reliably detect thrombosis of the portal venous system. SCOPE OF THE PROBLEM Variceal hemorrhage is associated with high morbidity and mortality. Furthermore, the management of gastrointestinal bleeding due to portal hypertension is associated with substantial economic costs. About 10% of all patients with acute upper gastrointestinal bleeding admitted to hospitals in the United States (an estimated 40,000 patients) have one or more episodes of gastrointestinal bleeding per year due to portal hypertension. The estimated annual cost of treatment of bleeding and bleeding-related complications is $30,000 per patient:" thus, gastrointestinal bleeding due to portal hypertension accounts for approximately $1.2 billion in health-care expenditures. In populations of patients with cirrhosis of the liver, the prevalence of esophageal varices is 25 to 70%, depending primarily on the prevalence of end-stage liver disease. Of

4 976 Mayo Clin Proc, October 1996, Vol 71 AzBF 250 mum Normal Az SF_ Azygos blood flow WHVP- Wedgedhepatic venous pretl8ure FHVP- Freehepatic venouspretl8ure PBF.Portal blood flow Cirrhosis Fig. I. Hepatic and portal pressures and flow in normal and cirrhotic liver. Azygos blood flow represents most of portosystemic collateral flow. patients with cirrhosis of the liver, 10 to 15% will have development of varices each year. Esophageal varices and congestive gastropathy will eventually develop in most patients with alcoholic cirrhosis." In a subgroup of patients, however, esophageal varices may stabilize or even regress. This phenomenon is most likely to occur in patients with alcoholic cirrhosis who discontinue drinking, but cessation of alcohol abuse is not a guarantee of variceal regression. One-third of patients with cirrhosis who have documented varices experience an episode of variceal hemorrhage. The incidence of bleeding is related to the severity ofthe underlying disease, and most bleeding episodes occur within the first 2 years after varices have been discovered." Currently, even with optimal management, 25 to 50% of patients die after their first hemorrhage. During the first 6 weeks after the initial bleeding episode, the risk of rebleeding is increased; the highest risk is during the first few days. The mean mortality associated with subsequent bleeding is about 25% because most high-risk patients die after the first hemorrhage; however, the mortality rate based on the modified Child classification remains the same: class A, 5%; class B, 25% or less; and class C, 50% or more." The risk of death becomes virtually constant about 6 weeks after hemorrhage. Therefore, unless effective therapeutic measures are taken during this high-risk period to prevent rebleeding, survival is unlikely to be affected because all therapeutic measures, except liver transplantation, have no beneficial effect on liver function. Because only a third of patients with varices experience bleeding episodes, the ability to identify those at highest risk of bleeding is of great clinical utility. Factors that seem to increase the risk of both initial and subsequent bleeding include continued alcohol abuse, level of liver decompensation based on the Child classification, large varices, red wale markings on varices at endoscopy, presence of gastric varices," changes in the velocity or reversal of portal flow as evaluated by Doppler echocardiography," and persistence or development of ascites." Of these variables, the factors shown to predict independently the risk of first variceal hemorrhage are Child class C, large varices, and red wale markings on the varices." TREATMENT OF The modalities available to treat variceal hemorrhage are pharmacologic agents, endoscopic therapy, balloon tamponade, transjugular intrahepatic portosystemic shunts (TIPS), surgical intervention, and liver transplantation. Liver transplantation, however, will not be discussed in this review. Pharmacologic Agents.-The most commonly used pharmacologic agents for the control of acute variceal hemorrhage are vasopressin, terlipressin, somatostatin, and octreotide; p-adrenergic blocking agents are used in the prevention of bleeding. Agents Used to Control Acute Variceal Hemorrhage. Vasopressin.-Until recently, vasopressin was the drug most widely used to control acute variceal hemorrhage.

5 Mayo Clio Proc, October 1996, Vol Intra-hepatic Cirrhosis liver SChistosomiasis Idiopathic portal hypertension Pre-hepatic Portal vein thrombosis Splenic vein thrombosis Fig. 2. Classification of portal hypertension based on site of increased resistance to portal blood flow. Vasopressin causes splanchnic arteriolar constriction, which results in reduced portal venous inflow and a consequent decrease in portal venous pressure of 20 to 30% as measured by the WHVP gradient." It also decreases azygos blood flow by 25% and reduces intravariceal pressure.f Because vasopressinhas a short half-life, it must be given by continuous intravenous infusion. It may be administered as a 20-U bolus intravenously over 20 minutes, followed by a continuous infusion of 0.4 U/min; however, it is frequently administered as a continuous infusion without a bolus dose. Unfortunately, vasopressin causes a high rate of cardiac complications in elderly persons, including coronary vasoconstriction, reduced cardiac output, myocardial ischemia and infarction, and potentially fatal arrhythmias, and thus treatment may need to be discontinued. Vasopressin can cause an increase in blood pressure with reflex bradycardia in the setting of active bleeding, which may lead to a false sense of security because these factors indicate improved hemodynamic stability. Furthermore, vasopressin acts on the kidney to prevent excretion of free water, which results in fluid overload, hyponatremia, and increasing ascites. Vascular complications related to generalized systemic vasoconstriction include mesenteric infarction, limb ischemia, and cerebrovascular accidents. In 25 to 30% of patients, use of vasopressin must be discontinued because of adverse effects, and the mortality related to vasopressin administration is approximately 5%.33 Overall, vasopressinhas proved to be no better than placebo relative to decreasing the need for emergency surgical treatment or transfusion requirement or in reducing mortality. Thus, enthusiasm for its use in the management of an acute gastrointestinal bleeding episode associated with portal hypertension is declining. Nitroglycerin.-Nitroglycerin has been used in combination with vasopressin in an attempt to attenuate the adverse cardiovascular side effects of vasopressin. Transdermally administered nitroglycerin increases the efficacy of vasopressin in controlling variceal hemorrhage but does not decrease cardiovascular complications. The optimal route of administration of nitroglycerin is intravenous with an initial dose of 40 ug/min, and incremental doses are given if the systolic blood pressure is higher than 100 mm Hg. Although 400 ug/min is considered the upper limit, we have found that it is impossible to increase the dose higher than 100 J.Lg/min without causing profound hypotension. The combination of vasopressin and nitroglycerin results in a reduced rate of cardiac complications and more frequent control of bleeding in comparison with vasopressin alone. 34 Terlipressin.-Terlipressin (glypressin), a synthetic triglycyl-lysine derivative of vasopressin, is slowly cleaved in vivo to release vasopressin. It has a longer duration of action and can be administered as a bolus intravenous injection of I to 2 mg every 4 to 6 hours. In controlled trials, terlipressin has been shown to control bleeding much more effectively than vasopressin, and transfusion requirements are lower. Ongoingtrials of terlipressinin combinationwith intravenous nitroglycerin therapy show encouraging preliminary results." Somatostatin.-Somatostatin, a 14-amino acid peptide, decreases splanchnic blood flow by a direct and selective action on mesenteric vascular smooth muscle as well as by reducing glucagon levels. It has a substantial advantage over vasopressin in that it does not produce systemic vasoconstriction. The short half-life of somatostatin (l to 2 minutes) necessitates administration as an initial intravenous bolus of

6 978 Mayo Clio Proc, October 1996, Vol ug, followed by a continuous intravenous infusion of 250 to 500 Ilg/h. Administration of somatostatin decreases the risk of early rebleeding." Several synthetic somatostatin analogues with longer half-lives have been produced and are characterized for their effectiveness in treating acute variceal bleeding. The most widely studied of the somatostatin analogues is the eight-amino acid peptide octreotide, which shares four amino acids with somatostatin; however, most studies that have evaluated the efficacy of somatostatin in the treatment of acute variceal hemorrhage have used somatostatin rather than the longer-acting analogue octreotide. Octreotide.-Octreotide administered subcutaneously has a half-life of 1 to 2 hours and has been shown to decrease portal pressure substantially. Although it has little or no effect on systemic vascular resistance'? and variable effects on intravariceal pressure, it decreases azygos blood flow considerably. Octreotide reduces portal pressure primarily by decreasing portal venous blood flow. It also severely blunts postprandial splanchnic hyperemia in patients with cirrhosis." This action is achieved through a direct vasoconstrictive effect or by an indirect effect mediated by inhibition of glucagon, which normally increases portal flow. Randomized clinical trials have shown octreotide to be more effective than placebo, vasopressin, or balloon tamponade in controlling acute variceal hemorrhage, and side effects are minimal. In a recent report, a 48-hour octreotide infusion and emergency sclerotherapy were equally effective in controlling variceal hemorrhage." In that study, octreotide was administered as an intravenous bolus of 50 ug, followed by a continuous infusion of octreotide at 50 Ilglh for the next 48 hours. Moreover, in patients undergoing sclerotherapy, octreotide infused at 25 j.lglh for 5 days decreased bleedingrelated mortality for the duration of infusion in comparison with infusion of placebo." Because of equal efficacy in comparison with vasopressin but much lower toxicity, octreotide may be the current drug of choice for early prehospital and in-hospital management of bleeding esophageal varices. Agents Used to Prevent Variceal Hemorrhage. /3- Adrenergic Blocking Agents.-p-Blockers reduce portal venous pressure by decreasing splanchnic blood flow, an outcome that causes a reduction in gastroesophageal collateral blood flow. The most experience has been obtained with propranolol, a nonselective pj- and P2-adrenergic blocking agent. Pj-Blockade reduces cardiac output and causes splanchnic vasoconstriction by reflex activation of cadrenergic receptors in the splanchnic circulation. Pz-Blockade induces splanchnic and peripheral vasoconstriction by eliminating P2-receptor-mediated vasodilatation and allowing unopposed e-adrenoreceptor mediated vasoconstriction. The reduction in splanchnic blood flow caused by these actions results in a decreased gastroesophageal collateral blood flow, as measured by azygos venous blood flow." A generally accepted theory is that propranolol should be standard prophylactic therapy for the first variceal hemorrhage. Propranolol is especially effective in patients shown to be compliant with therapy. Patients in whom the HVPG decreases to less than 12 mm Hg do not have bleeding from esophageal varices, and they also have decreased mortality." Patients with large varices, who have an increased risk of bleeding, benefit the most from P-blocker therapy. Ideally, the HVPG should be measured before propranolol is initiated; however, because of the invasive nature of the procedure, most clinicians do not routinely obtain this measurement. The aim of prophylactic therapy is to achieve the largest possible reduction in portal venous pressure gradient while avoiding toxic side effects. If portal pressure measurements are unavailable, the resting heart rate is used as a variable of response; the goal is to decrease the heart rate by 25% but to no less than 55 beats/min. Generally, propranolol is used as a long-acting preparation and titrated on a weekly basis to a maximal dosage of 320 mg/day; the mean dose is 160 mg/day, preferably administered in the evening. Nadolol, another nonselective p-adrenergic blocking agent, has a longer half-life than propranolol and can also be administered once daily. Because nadolol is primarily excreted by the kidneys, dosage adjustment is more reliable, and because it does not cross the blood-brain barrier, it is potentially less likely to cause central nervous system side effects. The initial daily dose of nadolol is 20 mg, and the maximal dose is 240 mg. Contraindications to P-blocker therapy include congestive heart failure, atrioventricular heart block, arrhythmias, severe chronic obstructive pulmonary disease, asthma, psychosis, and insulin-dependent diabetes mellitus. The major side effects include fatigue, impotence, depression, hypotension, bradycardia, sleep disorders, and cardiac failure. Because of the risk of recurrent bleeding after cessation of P-blocker therapy, the drug should be used indefinitely in patients with portal hypertension. No evidence has shown that use of P-blockers compromises the management of acute gastrointestinal bleeding in patients with portal hypertension by blunting the effects of reflex circulatory adjustments to hemorrhage. In approximately 20% of patients taking propranolol, the HVPG does not decrease. The unresolved question in the consideration of prophylactic Pblocker therapy is whether administering it to all patients with cirrhosis and varices is justifiable when only one-third of patients might experience variceal bleeding. The ideal candidate is probably the patient who has a high risk of bleeding (large varices and endoscopic red wale signs) and who can tolerate and will be compliant with therapy. Other Agents.-Of the other pharmacologic therapies, none have been used widely enough to be recommended other than in clinical trials for the prevention of gastrointesti-

7 Mayo Clin Proc, October 1996, Vol 71 nal bleeding in patients with portal hypertension. Evidence shows that the addition of nitrates-for example, isosorbide5-mononitrate-improves the protective effect of l3-blockers on variceal bleeding." Isosorbide-5-mononitrate may be a reasonable alternative for patients with contraindications or intolerance to propranolol. Recent evidence also demonstrates that long-term administration of spironolactone to patients with cirrhosis who do not have ascites causes a significant reduction in the HVPG due to a gradual, sustained volume contraction. Finally, a low sodium diet has been shown to cause a decrease in plasma volume, cardiac index, and portal pressure and may be recommended for all patients with portal hypertension. Endoscopic Therapy. Injection Sclerotherapy.-Injection sclerotherapy has been used for more than 50 years in the treatment of variceal bleeding. It is effective in controlling active bleeding and also decreases the risk of variceal rebleeding. The mechanism of action of sclerotherapy is believed to be through the induction of an intravariceal and paravariceal inflammatory reaction, with eventual fibrosis and obliteration of the varices. Several sclerosants have been used, including sodium tetradecyl sulfate, morrhuate sodium, ethanolamine, and ethanol. Usually, 2 ml (1 ml if injected paravariceally) of 1.5% sodium tetradecyl sulfate is injected at each site intravariceally in the distal 4 to 5 em of the esophagus where most variceal bleeding occurs. A maximal dose of 20 to 30 ml of sclerosant is used per session because the rate of complications associated with sclerotherapy is proportional to the volume of sclerosant used. The initial injection is in the variceal columns in the distal esophagus; the distance between injection sites on the same varix is approximately 2 em. Within 24 hours after the initial injection, submucosal sloughing and ulceration occur. During this time frame, the risk of variceal rebleeding after emergency sclerotherapy is highest. Care must be taken to ensure that not all the variceal columns are injected at the same level because subsequent scarring may result in an esophageal stricture. Of importance, however, the choice of sclerosant, intravariceal versus paravariceal injection, site of injection, and interval between injections have not been adequately studied, and the regimens used are essentially based on individual preference. Gastric varices are more difficult to treat endoscopically than esophageal varices because they are less discrete and usually form an intertwining network. Gastric varices in continuity with esophageal varices can be treated with injections just below the gastroesophageal junction, but isolated gastric varices in the fundus of the stomach are difficult to treat. Complications of injection sclerotherapy include deep esophageal ulcers that may be associated with severe bleeding, esophageal or gastric wall necrosis, mediastinitis, 979 esophageal strictures, nonspecific esophageal motility disorders, pseudodiverticula, and distal esophageal mucosal bridges. Pleural effusions are common after sclerotherapy. Rarely, adult respiratory distress syndrome, bronchoesophageal fistula, chylothorax, pneumothorax, or subcutaneous emphysema may occur. Local and distant abscesses and bacterial peritonitis have been reported after sclerotherapy, but routine antibiotic prophylaxis is usually unnecessary. Patients with cardiac defects who have a high risk for the development of infective endocarditis must receive antibiotic prophylaxis before sclerotherapy. Variceal Band Ligation.-Variceal band ligation is a relatively new technique for treating esophageal varices and has an efficacy equal to injection sclerotherapy in the treatment of acute variceal bleeding, with significantly fewer complications.v" Endoscopic variceal ligation (EVL) is done by using an endoscopic ligating device and overtube. The overtube, a plastic sheath that is 25 em in length and 20 mm in diameter and is usually mounted on an esophageal dilator, is inserted into the proximal esophagus. The overtube remains in the esophagus throughout the procedure and facilitates repeated removal and reinsertion of the endoscope. The varices are ligated individually; the approach is to begin with those just below the gastroesophageal junction and move proximally to about 7.5 cm above the gastroesophageal junction. All varices are ligated at least once, and large varices are ligated at separate points. Banding induces venous obstruction, mucosal inflammation, necrosis, and scar formation. The ulcers produced by the sloughing of banded varices are smaller and less likely to bleed than those occurring after injection sclerotherapy. Healing of these ulcers promotes fibrosis and variceal obliteration. Complications after EVL are significantly lower in comparison with those after sclerotherapy, and this may be related to the fact that EVL is a purely mechanical method of obliterating varices that has no systemic effect. Complications include superficial ulceration and dysphagia, esophageal strictures, and transient chest discomfort. Tissue Adhesive Injection.-Tissue adhesive injection is an extension of the technique of injection sclerotherapy with use of cyanoacrylate tissue adhesives for direct intravariceal injection."? It is especially valuable in the treatment of gastric fundal varices because these varices respond poorly to injection sclerotherapy. Toxicity of the adhesives is a concern, but early results suggest that tissue adhesives are effective in controlling variceal bleeding. Balloon Tamponade.-Balloon tamponade is a method for controlling variceal bleeding in which inflated esophageal and gastric balloons extrinsically compress the varices. The Sengstaken-Blakemore and Minnesota tubes are the most commonly used. Both tubes have esophageal and gastric balloons and a port for gastric decompression; however,

8 980 the Minnesota tube also has a port above the esophageal balloon for suction of secretions to prevent pulmonary aspiration. The Linton tube has a single large gastric balloon and is recommended for tamponade of bleeding gastric varices. When the balloon tamponade method is performed by experienced personnel, efficacy is greater than 80% for controlling active variceal bleeding." The drawback of balloon tamponade is that the period of compression should be limited to 24 hours or, rarely, 48 hours, and the rate of early rebleeding is high. Complications of balloon tamponade include pulmonary aspiration, esophageal ulceration, esophageal perforation or rupture, and asphyxiation from upper airway obstruction. Endotracheal intubation should be considered to protect the airway and prevent aspiration when balloon tamponade is used. In light of the major complications, balloon tamponade is generally indicated only when both pharmacologic treatment and emergency endoscopic therapy have failed. Transjugular Intrahepatic Portosystemic Shunts.-The TIPS is a recent modality introduced for the treatment of portal hypertension. With this procedure, an intrahepatic portosystemic shunt is created between the hepatic vein and an intrahepatic branch of the portal vein by placement of an expandable metallic stent with use of interventional radiologic techniques." Ideally, the TIPS should reduce the portal venous pressure gradient to less than 12 mm Hg. Shunt patency is confirmed on follow-up by using duplex Doppler ultrasound scanning. The risk of variceal bleeding after a TIPS procedure is approximately 10%; encephalopathy, which occurs in 25% of patients, is usually mild." The actual occurrence of encephalopathy is probably higher, however, because in many centers, patients receive lactulose prophylactically after placement of a TIPS. The benefits of a TIPS must be weighed against the risk of long-term stenosis, which is high." We recommend a TIPS for the control of variceal hemorrhage when two sessions of endoscopic therapy have failed to control the bleeding and for prevention of recurrent bleeding in patients awaiting liver transplantation in whom pharmacologic and endoscopic therapy treatments have failed. Placement of a TIPS may be best used as a bridge to liver transplantation in patients with recurrent variceal bleeding." Early complications associated with a TIPS include intraabdominal hemorrhage from perforation of the liver capsule or rupture of the portal vein wall, hemobilia, sepsis, portal vein thrombosis, early shunt occlusion, stent migration, cardiac failure due to the large increase in venous return to the right atrium after shunt insertion, and hemolysis." Late complications include hepatic encephalopathy and shunt stenosis. Of importance, a meticulous aseptic technique and prophylactic antibiotics should be used to prevent shunt infections. Large-volume paracentesis should be performed Mayo Clio Proc, October 1996, Vol 71 before a TIPS procedure if patients have tense ascites because large amounts of ascites displace the liver and make shunt placement technically more difficult. Surgical Therapy. Portosystemic Shunt Surgical Procedures.-The three types of shunt surgical procedures based on hemodynamic result are as follows: (1) nonselective shunts like the portacaval shunt, which completely decompress the entire portal venous system and divert all portal flow away from the liver; (2) selective shunts like the distal splenorenal shunt, which compartmentalize the portal venous system into a decompressed esophagogastric component and a high-pressure superior mesenteric-portal component that may continue to perfuse the liver; and (3) partial shunts like the calibrated portacaval shunt, which only partially decompress the entire portal venous system but have the potential of maintaining portal venous perfusion of the liver. A shunt operation decreases the risk of rebleeding better than any other therapy. Unfortunately, because of decreased hepatic perfusion and portosystemic shunting, the risk of hepatic encephalopathy is increased; however, it is less, at least during the short-term period, with distal splenorenal shunts in patients with nonalcoholic liver disease. A shunt should be considered for patients with good liver function who live a lengthy distance from tertiary-care centers and for those intolerant of, refractory to, or noncompliant with endoscopic or pharmacologic therapy, especially if bleeding is from gastric varices or from portal hypertensive gastropathy. When liver transplantation is a future possibility, attempts should be made to avoid a portacaval shunt because this procedure makes liver transplantation technically more difficult. Detailed discussions on surgical procedures for portal hypertension have been published.w" Esophageal Transection.-Use of esophageal transection has been relatively successful, particularly in the United Kingdom, for the treatment of variceal hemorrhage that persists despite endoscopic variceal therapy. It is comparable to injection sclerotherapy relative to both control of bleeding and mortality rates" but remains a second-line therapy because of its invasive nature and the increased cost of the surgical procedure. The major advantage of esophageal transection over shunting procedures is the decreased risk of encephalopathy. Because portal hypertension is not corrected, esophageal transection is less effective than shunt procedures in preventing rebleeding. CHOICE OF THERAPY Prevention of the First Variceal Hemorrhage.-The risk factors for variceal hemorrhage include continued alcohol use, poor liver function, portal venous pressure gradient higher than 12 mm Hg, and large varices with a wale sign. Thus, all patients should be cautioned against continued

9 Mayo Clin Proc, October 1996, Vol 71 alcohol use because ingestion of even small amounts may increase portal pressure." The only other intervention recommended to decrease the risk of the first hemorrhage is the use of the P-blocker propranolol. Patients in whom the HVPG has decreased to less than 12 mm Hg 3 months after institution of propranolol are most likely to benefit from continued use of propranolol. In those in whom the HVPG has not decreased at 3 months, use of the drug can be discontinued because such patients probably will not benefit from continued therapy. If the HVPG is not measured, patients must take propranolol indefinitely. In our practice, we prefer to have patients monitor their own resting heart rate and blood pressure for about 1 week before propranolol is instituted. We do not begin medication if compliance with monitoring of blood pressure and heart rate cannot be ensured or if the systolic blood pressure is usually lower than 100 mm Hg. Use of propranolol is discontinued if side effects are disabling or if the systolic blood pressure decreases to less than 90 mm Hg, an outcome that occurs often. Ideally, use of propranolol is continued for as long as the risk of variceal hemorrhage exists. Control of Acute Variceal Hemorrhage.-Because numerous treatment modalities are available for patients with varices, the physician must select the appropriate modality for each individual patient's problem. The aim of treatment is not only to control acute hemorrhage but also to prevent rebleeding, which occurs most often within 5 to 7 days. The preferred method for control of variceal hemorrhage is endoscopic therapy because it decreases the risk of early rebleeding." Octreotide after initial sclerotherapy further reduces the risk of recurrent variceal bleeding." Variceal band ligation has been shown to be as effective as sclerotherapy in controlling variceal hemorrhage." Because application of suction is an essential part of variceal ligation, this procedure may be difficult in the presence of active hemorrhage in that blood entering into the field obscures visualization. In the presence of active hemorrhage, endotracheal intubation is recommended to protect against aspiration and its consequences. In the setting of acute upper gastrointestinal hemorrhage, even if no active bleeding is present, esophageal varices are treated if no other potential site of bleeding is identified. Gastric varices, however, are not treated unless they are actively bleeding. Endoscopic therapy can control bleeding with a single session in about 70% of patients. A second session may be done within 24 hours in those patients in whom bleeding is inadequately controlled. The overall rate of control of acute variceal hemorrhage with endoscopic therapy is 90%. Balloon tamponade is performed for immediate control of variceal hemorrhage and to stabilize the patient when endoscopic or pharmacologic therapy is ineffective. In the 10% of patients whose bleeding cannot be controlled with 981 two endoscopic therapeutic sessions within 24 hours.f either an operation or a TIPS procedure is recommended. If endoscopic therapy cannot be done early enough, pharmacologic therapy is initiated. Somatostatin is effective in this setting and has few side effects.v-" Vasopressin in combination with nitroglycerin was our preferred method of pharmacologic control of acute hemorrhage until recently. Because of recent studies that have demonstrated the efficacy and safety of octreotide in comparison with vasopressin or rerlipressin." we prefer octreotide. The dosage is 25 to 50 llglh and is continued for 5 days in an effort to prevent rebleeding. In patients with ascites, diagnostic abdominal paracentesis should be performed to rule out spontaneous bacterial peritonitis (SBP). If tense ascites is present, largevolume therapeutic paracentesis with albumin replacement may also be indicated. Because patients with variceal hemorrhage have an increased risk for the development of SBP, 400 mg of oral norfloxacin therapy should be administered twice daily in an effort to prevent SBP. Prevention of Variceal Rebleeding.-After the acute variceal hemorrhage has been controlled, measures should be initiated to prevent repeated bleeding episodes, which occur in the vast majority of patients." The most widely used methods of preventing variceal rebleeding are endoscopic therapy and propranolol. The effectiveness of sclerotherapy in decreasing variceal rebleeding and blood transfusion requirement has been confirmed by a recent Veterans Affairs study." Although both endoscopic and pharmacologic methods are acceptable, we use endoscopic variceal ligation therapy as the initial modality for preventing variceal rebleeding. The ideal interval between consecutive sessions of variceal therapy has not been standardized, but we prefer to perform the second session of variceal ligation about 10 days after the initial session to control the index variceal hemorrhage. Subsequent sessions are done at approximately 2- to 3-week intervals until the varices are obliterated. After the varices have been obliterated, endoscopy is performed after 3 months and then every 6 to 12 months thereafter. Recurrent varices are treated by ligation. If no contraindications exist, use of propranolol or a combination of propranolol and isosorbide dinitrate is an acceptable alternative to endoscopic therapy. A combination of propranolol and variceal sclerotherapy has been shown to be slightly more effective in preventing variceal rebleeding than sclerotherapy alone.p Thus, a combination of Pblockers and variceal ligation may prove to be more effective than variceal ligation alone. In patients receiving P-blockers or endoscopic therapy, the chance of rebleeding within 1 year can be as high as 75% Because approximately four or five endoscopic sessions over 3 to 6 months are needed before varices are

10 982 Mayo Clin Proc, October 1996, Vol 71 Table3.-Current Choice of Treatment of Variceal Hemorrhage* Clinical setting Prevention of first hemorrhage Controlof acutehemorrhage Prevention of rebleeding First-line Propranolol Endoscopy? Octreotide Endoscopy Propranolol Treatment Second-line Balloon tamponade TIPS Surgery Childclass A: DSRS Childclass B:? DSRS?TIPS Childclass C: TIPS OLT *DSRS = distal splenorenal shunt; OLT = orthotopic liver transplantation; TIPS = transjugular intrahepatic portosystemic shunt. obliterated, we do not consider rebleeding within this period an indicator of failure of endoscopic therapy. Nonetheless, even one episode of rebleeding associated with hypovolemic shock or two episodes of esophageal variceal rebleeding that result in a decrease in the hemoglobin concentration of more than 2 g/dl warrant consideration of a shunt procedure. If the patient has good liver function, a surgically created shunt should be used, but if liver function is poor, a TIPS is recommended as a bridge to orthotopic liver transplantation. SUMMARY Gastrointestinal bleeding as a result of portal hypertension is a major cause of mortality and morbidity in patients with liver disease. Thus, our current recommendations for the treatment of variceal hemorrhage (Table 3) are as follows: propranolol for the prevention of the first variceal hemorrhage; endoscopic therapy, with octreotide being the preferred pharmacologic modality, for the control of acute variceal hemorrhage; and endoscopic therapy or propranolol for the prevention of recurrent hemorrhage. A TIPS is recommended for the control of acute variceal hemorrhage after two endoscopic sessions within 24 hours have failed to control bleeding and to prevent rebleeding in patients with recurrent variceal hemorrhage who are awaiting orthotopic liver transplantation because of failed endoscopic or pharmacologic therapy. REFERENCES 1. Bosch J, Pizcueta P, Feu F, Fernandez M, Garcia-Pagan Je. Pathophysiology of portal hypertension. Gastroenterol Clin North Am 1992 Mar; 21: Abelmann WHo Hyperdynamic circulation in cirrhosis: a historical perspective [editorial]. Hepatology 1994; 20: Bomzon A, Blendis LM. The nitric oxide hypothesis and the hyperdynamic circulation in cirrhosis. Hepatology 1994; 20: Groszmann RJ. Hyperdynamic circulation of liver disease 40 years later: pathophysiology and clinical consequences [editorial]. Hepatology 1994; 20: Sieber CC, Lopez-Talavera JC, Groszmann RJ. Role ofnitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats. Gastroenterology 1993; 104: Sieber CC, Groszmann RJ. In vitro hyporeactivity to methoxamine in portal hypertensive rats: reversal by nitric oxide blockade. Am J Physiol 1992; 262:G996-G Kiel JW, Pitts V, Benoit IN, Granger DN, Shepherd AP. Reduced vascular sensitivity to norepinephrine in portal-hypertensive rats. Am J Physiol 1985; 248:0192-G Hartleb M, Moreau R, Cailmail S, Gaudin C, Lebrec D. Vascular hyporesponsiveness to endothelin I in rats with cirrhosis. Gastroenterology 1994; 107: Bruix J, Bosch J, Kravetz D, Mastai R, Rodes J. Effects of prostaglandin inhibition on systemic and hepatic hemodynamics in patients with cirrhosis of the liver. Gastroenterology 1985; 88: Kravetz D, Arderiu M, Bosch J, Fuster J, Visa J, Casamitjana R, et a1. Hyperglucagonemia and hyperkinetic circulation after portocaval shunt in the rat. Am J Physiol 1987; 252:G257-G Pak JM, Lee SS. Glucagon in portal hypertension. J Hepatol 1994; 20: Claria J, Jimenez W, Ros J, Asbert M, Castro A, Arroyo V, et a1. Pathogenesis of arterial hypotension in cirrhotic rats with ascites: role of endogenous nitric oxide. Hepatology 1992; 15: Lopez-Talavera JC, Merrill WW, Groszmann RJ. Tumor necrosis factor a: a major contributor to the hyperdynamic circulation in prehepatic portal-hypertensive rats. Gastroenterology 1995; 108: Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985; 1: Asbert M, Gines A, Gines P, Jimenez W, Claria J, Salo J, et a1. Circulating levels of endothelin in cirrhosis. Gastroenterology 1993; 104: Moore K, Wendon J, Frazer M, Karani J, Williams R, Badr K. Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome. N Engl J Med 1992; 327: Gondo K, Veno T, Sakamoto M, Sakisaka S, Sata M, Tanikawa K. The endothelin-i binding site in rat liver tissue: light- and electronmicroscopic autoradiographic studies. Gastroenterology 1993; 104: Kamath PS, Grabau C, Ward L, Tyee GM, Miller VM, Rorie DK. Increased intrahepatic resistance in portal hypertension is mediated by endothelin [abstract]. Hepatology 1993; 18(Program Issue): 282A 19. Lebrec D. Methods to evaluate portal hypertension. Gastroenterol Clin North Am 1992 Mar; 21: Groszmann RJ, Bosch J, Grace ND, Conn HO, Garcia-Tsao G, Navasa M, et a1. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990; 99: Gertsch P, Fischer G, Kleber G, Wheatley AM, Geigenberger G, Sauerbruch T. Manometry of esophageal varices: comparison of an

11 VARICEAL HEMORRH AGE Mayo Clin Proc, October 1996, Vol 71 endoscopic balloon technique with needle puncture. Gastroenterology 1993; 105: Bosch 1, Groszmann RI. Measurement of azygos venous blood flow by a continuous thermal dilution technique: an index of blood flow through gastroesophageal collaterals in cirrhosis. Hepatology 1984; 4: Garcia-Pagan IC, Feu F, Castells A, Luca A. Hermida RC, Rivera F. et al. Circadian variations of portal pressure and variceal hemorrhage in patients with cirrhosis. Hepatology 1994; 19: Vilgrain V. Lebrec D. Menu Y. Scherrer A, Nahum H. Comparison between ultrasonographic signs and the degree of portal hypertension in patients with cirrhosis. Gastrointest Radiol 1990; 15: Cello JP, Grendell IH, Crass RA, Weber TE. Trunkey DD. Endoscopic sclerotherapy versus portacaval shunt in patients with severe cirrhosis and acute variceal hemorrhage: long-term followup. NEnglJMed 1987; 316: Burroughs AK, McCormick PA. Natural history and prognosis of variceal bleeding. Baillieres Clin Gastroenterol 1992; 6: Kleber G, Sauerbruch T, Fischer G, Geigenberger G, Paumgartner G. Redu ction of tr an smural oeso phageal va ricea l pre ssur e by metoclopramide. J Hepatol 1991; 12: Gaiani S, Bolondi L, Li Bassi S, Zironi G, Siringo S, Barbara L. Prevalence of spontaneous hepatofugal portal flow in liver cirrhosis: clinical and endoscopic correlation in 228 patients. Gastroenterology 1991; 100: Conn HO, Lindenmuth WW. May CJ, Ramsby GR. Prophylactic portacaval anastomosis. Medicine 1972; 51: North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices: a prospective multicenter study. N Engl 1 Med 1988; 319: Bosch J, Navasa M. Garcia-Pagan JC, DeLacy AM, Rodes J. Portal hypertension. Med Clin North Am 1989 Jul; 73: Bosch 1. Bordas 1M, Mastai R, Kravetz D, Navasa M, Chesta 1, et al. Effects of vasopressin on the intravariceal pressure in patients with ci rrhosis: co mpar ison wit h the effec ts on port al pre ssur e. Hepatology 1988; 8: Westaby D. The management of active variceal bleeding. J Hepatol 1993; 17(SuppI2):S34-S Bosch J, Groszmann RJ, Garcia-Pagan JC, Teres J, Garcia-Tsao G, Navasa M, et al. Association of transdermal nitroglycerin to vasopressin infusion in the treatment of variceal hemorrhage: a placebocontrolled clinical trial. Hepatology 1989; 10: Lin HC, Tsai YT, Lee FY. Chang TT, Wang SS, Lay CS, et al. Systemic and portal haemodynamic changes following triglycllysine vasopressin plus nitroglycerin administration in patients with hepatitis B-related cirrhosis. J Hepatol 1990; 10: Imperiale TF, Teran JC, McCullough AJ. A meta-analysis of somatostatin versus vasopressin in the management of acute esophageal variceal hemorrhage. Gastroenterology 1995; 109: Lin HC, Tsai YT, Lee FY, Lee SD. Hsia HC, Lin WJ,etai. Hemodynamic evaluation of octreotide in patients with hepatitis B-related cirrhosis. Gastroenterology 1992; 103: Buonamico P, Sabba C, Garcia-Tsao G, Berardi E. Antonica G, Ferraioli G, et al. Octreotide blunts postprandial splanchnic hyperemia in cirrhotic patients: a double-blind randomized echo-doppler study. Hepatology 1995; 21: Sung JJ, Chung SC, Lai CW, Chan FK, Leung JW, Yung MY, et al. Octreot ide infu sion or emergency sc lero therapy for var icea l haemorrhage. Lancet 1993; 342: Besson I, Ingrand P, Person B, Boutroux D, Heresbach D, Bernard P, et al. Sclerotherapy with or without octreotide for acute variceal bleeding. N Engl J Med 1995; 333: Feu F, Bordas 1M, Luca A, Garcia-Pagan JC, Escorsell A, Bosch J, et al. Reduction of variceal pressure by propranolol: comparison of the effects on portal pressure and azygos blood flow in patients with cirrhosis. Hepatology 1993; 18: Garcia-Pagan lc, Feu F, Bosch 1, Rodes 1. Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis: a randomized controlled study. Ann Intern Med 1991; 114: Stiegmann GV, Goff I S. Michaletz-Onody PA, Korula 1, Lieberman D, Saeed ZA. et al. Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices. N Engl 1 Med 1992; 326: Gimson AE, Ramage IK, Panos MZ, Hayllar K, Harrison PM, Williams R. et al. Randomised trial of variceal banding ligation versus injection sclerotherapy for bleeding oesophageal varices. Lancet 1993; 342: Laine L, el-newi hi HM, Migikov sky B, Sloane R, Garcia F. Endoscopic ligation compared with sclerotherapy for the treatment of bleeding esophageal varices. Ann Intern Med 1993; 119:1-7 Lo GH, Lai KH, Cheng IS, Hwu IH, Chang CF, Chen SM, et al. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology 1995; 22: Soehendra N, Nam VC, Grimm H, Kempeneers I. Endoscopic obliteration of large esoph agogastric varices with bucrylate. Endoscopy 1986; 18:25-26 Panes 1, Teres 1, Bosch I. Rodes J. Efficacy of balloon tamponade in treatment of bleeding gastric and esophageal varices: results in 151 consecutive episodes. Dig Dis Sci 1988; 33: Zemel G, Katzen BT, Becker GJ. Benenati I F. Sallee DS. Percutaneous transjugular portosystemic shunt. lam A 1991; 266: Rossie M, Haag K, Ochs A, Sellinger M, Noldge G, Perarnau 1-M, et al. The transjugular intrahepatic portosystemic stent-shunt procedure for variceal bleeding. N Engl 1 Med 1994; 330: Lind CD, Malisch TW, Chong WK, Richards WO, Pinson CW, Meranze SG, et al. Incidence of shunt occlusion or stenosis following transjugular intrahepatic portosystemic shunt placement. Gastroenterology 1994; 106: Kamath PS, McKusick MA. Transjugular intrahepatic portosystemic shunts: a note of caution [editorial). Gastroenterolog y 1994; 106: Freedman AM, Sanyal AI, Tisnado 1. Cole PE, Shiffman ML, Luketic VA, et al. Complications of transjugular intrahepatic portosystemic shunt: a comprehensive review. Radiographies 1993; 13: Rikkers LF, Sorrell WT, l in G. Which portosystemic shunt is best? Gastroenterol Clin North Am 1992 Mar; 21: Collins IC, Rypins EB, Sarfeh II. Narrow-diameter portacaval shunts for management of variceal bleeding. World 1 Surg 1994; 18: Burroughs AK, Hamilton G, Phillips A, Mezzanotte G, McIntyre N. Hobbs KEF. A comparison of sclerotherapy with staple transection of the esophagus for the emergency control of bleeding from esophageal varices. N Engl 1 Med 1989; 321: Luca A, Feu F, Garcia-Pagan JC, Lopez-Talavera IC, Caballerfa 1, Bosch 1. et al. Ethanol consumption worsens hepatic hemodynamics in patients with alcoholic cirrhosis and portal hypertension [abstract). Hepatology 1993; 18(Program Issue):108A Larson AW, Cohen H, Zweiban B, Chapman D, Gourdji M, KorulaJ, et al. Acute esophageal variceal sclerotherapy: results of a prospective randomized controlled trial. l AMA 1986; 255: Planas R, Quer IC, Boix 1, Canet 1, Armengol M. Cabre E, et al. A pros pec tive ran domized tr ial compa ring somatos tati n and sclerotherapy in the treatment of acute variceal bleeding. Hepatology 1994; 20: Silvain C, Carpentier S, Sautereau D. Czernichow B, Metreau 1M, Fort E, et al. Terlipressin plus transdermal nitroglycerin vs octreotide in the control of acute bleed ing from esophageal varices: a multicenter randomized trial. Hepatology 1993; 18:61-65 Veterans Affairs Coo perative Var iceal Sclerotherapy Group. Sclerotherapy for male alcoholic cirrhotic patients who have bled from esophageal varices: results of a randomized, multicenter clinical trial. Hepatology 1994; 20: Jensen LS, Kramp N. Propranolol in prevention of rebleeding from oesophageal varices during the course of endoscopic sclerotherapy. Scand 1 Gastroenterol 1989; 24: Burroughs AK, Jenkins WI, Sherlock S, Dunk A, Walt RP, Osuafor TO, et al. Controlled trial of propranolol for the prevention of recurrent variceal hemorrhage in patients with cirrhosis. N Engl J Med 1983; 309: