Portal hypertension is the main complication of cirrhosis

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1 GASTROENTEROLOGY 2001;120: Current Management of the Complications of Cirrhosis and Portal Hypertension: Variceal Hemorrhage, Ascites, and Spontaneous Bacterial Peritonitis GUADALUPE GARCIA TSAO Gastroenterology Service, VA Connecticut Healthcare System, and Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut Portal hypertension is the main complication of cirrhosis because it is directly responsible for two of its most common and potentially lethal complications: variceal hemorrhage and ascites. Cirrhosis leads to both an increase in hepatic sinusoidal pressure and an increase in portal pressure gradient, that is, the pressure difference between the portal vein and the systemic veins (hepatic veins or inferior vena cava). Pressure increases initially as a consequence of an increased resistance to portal flow that occurs at all levels of the intrahepatic vascular bed, i.e., at the branches of the portal vein within the liver, at the sinusoids, and at the hepatic venous outflow tract. This obstruction to flow is mostly caused by an architectural distortion of the liver secondary to fibrous tissue and regenerative nodules. However, studies in the perfused cirrhotic rat liver indicate that, in addition to this structural resistance to blood flow, there is a primary increase in intrahepatic vascular tone, amenable to pharmacologic manipulation. 1 This reversible component accounts for about 20% 30% of the increased intrahepatic resistance. An elevated portal pressure gradient results in the formation of portosystemic collaterals. These collaterals are insufficient to decompress the portal venous system because their vascular resistance, although lower than that of the intrahepatic vasculature, is higher than normal portal resistance. 2 Even when 100% of portal blood is being shunted away from the portal venous system through collaterals, portal pressure remains elevated. This is not only due to the resistance that collaterals themselves offer to portal flow, but is also due to an increase in portal venous inflow. 3 This increased portal venous inflow is the result of splanchnic arteriolar vasodilatation that occurs concomitant with the formation of collaterals and occurs not only in the splanchnic circulation but also in the systemic circulation. Therefore, an increased portal pressure gradient results from both an increase in resistance to portal flow (intrahepatic and collateral) and an increase in portal blood inflow (Figure 1). The normal portal pressure gradient is 3 6 mm Hg. In the early stages of cirrhosis, patients have a normal portal pressure gradient. As the disease progresses, portal pressure increases to abnormal levels; however, a minimum threshold level of at least 10 mm Hg is necessary for gastroesophageal varices to develop. 4,5 An elevated sinusoidal pressure results in the formation of ascites. A minimum portal pressure gradient of mm Hg has also been established for the development of ascites. 6,7 In fact, the concept of clinically significant portal hypertension was recently defined as an increase in the portal pressure gradient to a threshold above 10 mm Hg. 8 Efflux of fluid from the intravascular (sinusoidal) space into the peritoneal cavity would be a self-limited process once the intravascular space became depleted. However, formation of ascites is a continuous process because there is constant replenishment of the intravascular volume. This is a result of sodium and water retention that occurs in response to the systemic vasodilatation present in cirrhosis. This vasodilatation leads to a decrease in effective blood volume and to activation of endogenous antinatriuretic and vasoconstrictive systems, specifically the renin-angiotensin-aldosterone system and the sympathetic nervous system, that lead to sodium and water retention. 9 Therefore, as shown in Figure 1, the two main complications of cirrhosis, varices and ascites, are the result of intrahepatic, splanchnic, and systemic hemodynamic alterations. Rational management of these complications Abbreviations used in this paper: EVL, endoscopic variceal ligation; HRS, hepatorenal syndrome; HVPG, hepatic venous pressure gradient; ISMN, isosorbide mononitrate; LVP, large-volume paracentesis; NO, nitric oxide; PCD, postparacentesis circulatory dysfunction; PMN, polymorphonuclear cell(s); PVS, peritoneovenous shunt; SBP, spontaneous bacterial peritonitis; TIPS, transjugular intrahepatic portosystemic shunt by the American Gastroenterological Association /01/$35.00 doi: /gast

2 February 2001 MANAGEMENT OF THE COMPLICATIONS OF CIRRHOSIS 727 Figure 1. Pathogenesis of portal hypertension and its two main complications: varices and ascites. should be based on the correction or amelioration of these alterations. Variceal Hemorrhage Gastroesophageal varices are the most important portosystemic collaterals because of their propensity to rupture, constituting the most dramatic and lethal complication of cirrhosis, variceal hemorrhage. Gastroesophageal varices are present in approximately 50% of cirrhotic patients. Their presence correlates with the severity of liver disease; while only 40% of patients with Child A disease have varices, they are present in 85% of Child C patients. 10 Patients with gastroesophageal varices develop variceal hemorrhage at a rate of 10% 30% per year. Although a threshold portal pressure of mm Hg is necessary for the development of varices, once varices develop the risk of rupture depends on the diameter of the varices, rather than on the degree of portal hypertension. Variceal wall tension is probably the main factor that determines variceal rupture. Besides vessel diameter, one of the determinants of variceal wall tension is the pressure within the varix, which is directly related to the portal pressure gradient. Therefore, a reduction in portal pressure gradient should lead to a decrease in variceal wall tension and to a decrease in the risk of rupture. This has been confirmed in clinical studies that have shown that variceal hemorrhage does not occur when the portal pressure gradient is reduced to values under the threshold level of 12 mm Hg. 7,11 In fact, it has been shown that the risk of bleeding decreases significantly with reductions in portal pressure gradient 20% from baseline. 12 Rationale for Different Therapeutic Maneuvers The different treatment options for varices and variceal hemorrhage, placed in the context of their pathogenesis, are depicted in Figure 2. Pharmacologic therapy. Reduction in portal pressure gradient can be achieved by using drugs that reduce intrahepatic resistance and/or drugs that reduce portal venous inflow. Correcting the increased intrahepatic resistance. The vascular, reversible component of the increased intrahepatic resistance is mainly the result of a deficit of the vasodilator nitric oxide (NO) in the liver microcirculation. 13,14 However, an increased sensitivity to endogenous vasoconstrictors (e.g., adrenaline and angiotensin) also plays an important role. 15 Therefore, drugs that increase the delivery of NO to the intrahepatic circulation, such as nitrates, and drugs that block adrenergic activity (e.g., prazosin, clonidine) or that block angiotensin (e.g., captopril, losartan, irbesartan) should be able to reduce the portal pressure gradient. In studies performed in the isolated perfused cirrhotic rat liver, the greatest reduction in perfusion resistance (approximately 30% of the increased resistance) is observed after infusion of nitroprusside, an NO donor. 1 In hemodynamic studies performed in patients with cirrhosis, administration of nitrates, prazosin, 22,23 clonidine, losartan, 28 and irbesartan 29 has resulted in significant reductions in hepatic venous pressure gradient (HVPG), an indirect measure of the portal pressure gradient. In studies in which these agents have been administered for 7 days or more, 21 23,26 31 the median reduction in HVPG is approximately 17%. Unfortunately, in vivo, venodilators act not only on the intrahepatic circulation, as would be ideal, but also exert a vasodilatory effect on the systemic and portocollateral circulation. This vasodilatation leads to arterial hypotension, which Figure 2. Treatment options for variceal hemorrhage placed in the context of its pathogenesis. Although theoretically (and in vitro) the mechanism of action of venodilators is a reduction in intrahepatic resistance, in vivo the action seems to be through reflex splanchnic vasoconstriction.

3 728 GUADALUPE GARCIA TSAO GASTROENTEROLOGY Vol. 120, No. 3 is frequently symptomatic. 16,18,29 In several of these studies, a direct correlation has been demonstrated between the decrease in arterial pressure and the decrease in HVPG This suggests that, in vivo, vasodilators decrease portal pressure mainly through a decrease in portal blood flow secondary to reflex splanchnic vasoconstriction that occurs in response to arterial hypotension. Additionally, as shown in Figure 1, aggravating vasodilatation can lead not only to a significant and symptomatic hypotension but also to a further decrease in effective arterial blood volume and activation of endogenous vasoactive systems leading to sodium retention and accumulation of ascites. In fact, long-term administration of prazosin has been associated with the development of salt retention, ascites, and edema, 22,23 and administration of the angiotensin-receptor antagonist irbesartan has been associated with a decrease in creatinine clearance. 29 Correcting the increased portal venous inflow. Endothelial vasodilators play a major role in the development of the vasodilatory and hyperdynamic circulatory state of cirrhosis. Of these, an excess production of NO in the systemic and splanchnic arterial beds appears to play the major role. This has been demonstrated in studies performed in isolated arteries and in perfused superior mesenteric arterial beds of portal hypertensive and cirrhotic animals. 36 Arteries are hyporesponsive to vasoconstrictors, and this hyporesponsiveness can be overcome by the use of NO synthase inhibitors. 32,36 Administration of NO blockers has not resulted in a reduction in portal pressure because the reduction in portal venous inflow induced by NO blockers is offset by an increase in intrahepatic and portocollateral resistance. 37 Pharmacologic therapy aimed at correcting the increased portal venous inflow is based on the use of splanchnic vasoconstrictors, such as -adrenergic blockers, vasopressin, and somatostatin, all of which have been shown to reduce HVPG significantly. Because vasopressin and somatostatin can only be administered intravenously, their use is restricted to the acute setting, whereas -adrenergic blockers are used in the long-term treatment of portal hypertension. -Adrenergic blockers reduce portal venous inflow by two mechanisms: by decreasing cardiac output (through blockade of 1 receptors) and by producing splanchnic vasoconstriction (through 2 -blockade and unopposed -adrenergic activity at the splanchnic vasculature). Predictably, selective 1 -adrenergic blockers decrease HVPG to a lesser degree than nonselective ( 1 - and 2 -) blockers. 38,39 Therefore, it is important that nonselective -adrenergic blockers, such as propranolol, nadolol, or timolol, be used in the therapy of portal hypertension. The median reduction in HVPG after administration of nonselective -blockers is approximately 15%. 11,38,40 43 In a study in which HVPG was measured 120 minutes after oral administration of propranolol, a third of the patients showed a reduction in HVPG 10% from baseline and only 15% of the patients showed a reduction of 20% from baseline. 41 The reduction in portal pressure induced by -blockers is smaller than the blocker induced reduction in portal blood inflow. This is due to a concomitant increase in collateral resistance secondary to the reduction in collateral diameter that results from the reduction in blood flow. 44 This decrease in collateral flow and diameter represents an added beneficial effect of -blockers (not assessable by a reduction in portal pressure), which can explain the efficacy of -blockers in clinical trials in face of an only modest portal pressure reducing effect. As could be predicted, -blockers induce a greater reduction in portal pressure in patients without varices than in patients with varices, 45 and their usefulness in the prevention of the development of varices is currently under evaluation (Table 1). Vasopressin is the most potent splanchnic vasoconstrictor. It reduces blood flow to all splanchnic organs, thereby leading to a decrease in portal venous inflow and a decrease in portal pressure. Vasopressin (and its analogue terlipressin) not only reduces portal pressure but has also been shown to reduce collateral flow and variceal pressure. 46,47 Unfortunately, the clinical usefulness of vasopressin is limited by its multiple side effects that are related to splanchnic vasoconstriction (e.g., bowel ischemia) and to systemic vasoconstriction (e.g., hypertension, myocardial ischemia). Terlipressin is a synthetic analogue of vasopressin that has a longer biological activity and significantly fewer side effects than vasopressin. Somatostatin and analogues such as octreotide and lanreotide also cause splanchnic vasoconstriction at pharmacologic doses. Although it has been considered that this effect is caused by an inhibition of the release of vasodilatory peptides (mainly glucagon), recent studies in humans 48,49 and in isolated mesenteric arterial beds 50 suggest that octreotide has a local vasoconstrictive effect. Bolus injections of both somatostatin and octreotide cause marked transient reductions in portal pressure. 49,51 After a bolus injection, a mild reduction in portal pressure is maintained with the continuous infusion of somatostatin 51 ; however, the continuous infusion of octreotide does not maintain or result in any reduction in portal pressure. 49 One of the most important effects of somatostatin and analogues is a blunting of postprandial

4 February 2001 MANAGEMENT OF THE COMPLICATIONS OF CIRRHOSIS 729 Table 1. Therapies for Varices and Variceal Hemorrhage Indication First-line therapy Second-line therapy Third-line therapy Under evaluation Not recommended Prevention of the development of varices Nonselective -blockers Prevention of first variceal hemorrhage a Nonselective -blockers?evl b -Blockers nitrates EVL Nitrates alone TIPS/shunt surgery Sclerotherapy Treatment of acute variceal hemorrhage Endoscopic (EVL or sclerotherapy) and/or drug therapy, (somatostain, terlipressin) TIPS/shunt surgery Balloon tamponade c Endoscopic adjuvant somatostatin analogues (octreotide, lanreotide) Octreotide alone Prevention of variceal rebleeding Nonselective -blockers or EVL EVL drug therapy ( -blockers nitrates) TIPS/shunt surgery -Blockers nitrates Sclerotherapy a In patients with moderate to large-sized varices. b In patients with high-risk varices who have contraindications or are intolerant to -blockers. c To be used as a bridge to TIPS or shunt surgery. hyperemia, the abrupt increase in portal pressure that occurs after a meal. 52 It has been demonstrated that, comparable to a meal, blood in the stomach induces postprandial hyperemia, 53 and this may be a major mechanism by which somatostatin and analogues prevent early variceal rebleeding. The absence of side effects of somatostatin and analogues represents a major advantage over other vasoconstrictive agents, allowing them to be administered for a longer period of time. Acting on both resistance and flow. The combination of intrahepatic vasodilators and splanchnic vasoconstrictors should result in an additive portal pressure reducing effect. This was first demonstrated in a hemodynamic study performed in cirrhotic patients in which the addition of nitroglycerin to vasopressin led to further reduction in HVPG that was not associated with a further decrease in portal flow. 54 This observation suggested that the additional reduction in HVPG induced by nitrates resulted from a decrease in intrahepatic resistance. Long-term hemodynamic studies in which patients have received a combination of propranolol with nitrates (either isosorbide mononitrate or isosorbide dinitrate) have shown the same results, i.e., that the addition of nitrates further enhances the portal pressure reducing effect of propranolol. The median HVPG reduction with combination therapy is approximately 20%. 42,43,55,56 Propranolol has also been administered together with other vasodilators such as prazosin. In a study comparing a combination of propranolol plus isosorbide mononitrate vs. propranolol plus prazosin, reduction in HVPG with the propranolol/prazosin combination (24%) was significantly greater than that obtained with the propranolol/isosorbide mononitrate combination (16%). 56 However, the propranolol/prazosin combination was associated with more side effects, specifically fluid retention and/or symptomatic hypotension. Carvedilol is an interesting new nonselective blocker with additional anti 1 -adrenergic activity that could potentially act by both reducing portal blood inflow ( -blocker effect) and intrahepatic resistance (antiadrenergic effect). In fact, a study that compared it with propranolol showed that a single carvedilol dose of 25 mg produced a significantly greater reduction in HVPG than intravenous administration of propranolol (21% vs. 13%, respectively). Unfortunately, carvedilol has been shown to cause a significant drop in both mean arterial pressure and peripheral resistance, which could have a negative impact in the long-term outcome of cirrhotic patients. 57,58 Acting on blood volume. Peripheral vasodilatation leads to activation of endogenous neurohumoral systems that lead to sodium retention and expansion of the plasma volume. In turn, expansion of the plasma volume plays a major role in the development of the hyperdynamic circulatory state that maintains an elevated portal pressure. Low-sodium diet and spironolactone have been shown to reduce portal pressure in patients with cirrhosis, 59,60 perhaps by reducing the circulating blood volume and thereby the splanchnic blood volume. However, this therapy has been associated with marked increases in plasma renin activity indicative of a decrease in effective blood volume that could be potentially deleterious. Portosystemic shunts. Portal hypertension can be corrected by creating a communication between the

5 730 GUADALUPE GARCIA TSAO GASTROENTEROLOGY Vol. 120, No. 3 hypertensive portal system and low-pressure systemic veins, bypassing the liver, i.e., the site of increased resistance (Figure 2). 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 portosystemic shunt (TIPS). 61 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. Endoscopic therapy. Endoscopic sclerotherapy and endoscopic variceal ligation (EVL) are non portal pressure-reducing methods to treat varices. Sclerotherapy consists of the injection of a sclerosant agent into or next to a varix with the objective of producing thrombosis of the varix and/or inflammation of the surrounding tissue. EVL 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 both can achieve variceal obliteration, varices will eventually recur. Complications of endoscopic therapy are related mainly to the development of esophageal ulceration and strictures, significantly more frequent after sclerotherapy than after EVL. Treatment of the Different Clinical Settings Mortality of an episode of variceal hemorrhage ranges between 30% and 50%. Most deaths occur after early rebleeding, which occurs within the first week of admission, constituting a major determinant of prognosis. Treatment of variceal hemorrhage should be essentially preventive. Patients who have not bled from varices require treatment to prevent bleeding. Patients who are bleeding from varices require not only therapies to stop the acute hemorrhage but also to prevent early and late rebleeding. The therapeutic maneuvers mentioned in the previous section will be placed in perspective depending on the specific clinical setting and based on evidence in the literature, mainly from randomized clinical trials and meta-analyses of these trials, as well as on the results of the most recent Baveno consensus conference. 8 These therapies are summarized in Table 1. Prevention of first variceal hemorrhage. Candidates are patients at a high risk of bleeding. Three factors identify these patients: large variceal size, presence of red wale markings on the varices, and severe liver failure. 62 Most trials on primary prevention of variceal hemorrhage have included patients with large varices. Regarding pharmacologic therapy, the results of a meta-analysis of 11 trials evaluating nonselective blockers in the prevention of first variceal hemorrhage have been reported recently. 63 Overall, the bleeding rate in controls is 25% and is significantly reduced to 15% in -blocker treated patients after a median follow-up of 24 months. Mortality rate is also lower in the -blocker group (23%) than the control group (27%); however, this difference does not achieve statistical significance. This meta-analysis also analyzes the effect of -blockers as a function of variceal size. The risk of first variceal bleeding in patients with large or medium-sized varices is significantly reduced by -blockers (30% in controls and 14% in -blocker treated patients). In patients with small varices, there is a tendency for a reduction in first hemorrhage (7% in controls and 2% in -blocker treated patients), but the number of patients and the rate of first bleeding is too low to achieve statistical significance. In another meta-analysis based on individual patient data, 64 the beneficial effect of -blockers was present in patients both with and without ascites and in patients with and without a poor liver function and was associated with a significant reduction in bleeding-related deaths. The frequency of side effects of -blockade in prophylactic trials is approximately 15%; however, the only double-blind placebo-controlled trial 65 showed a 14% rate of side effects in the propranolol group and a 6% rate in the placebo group. The most common side effects are lightheadedness, fatigue, and cold extremities. Some of these side effects disappear with time or after a reduction in the dose of the -blocker. Isosorbide mononitrate (ISMN) has been shown in one study to be as effective as propranolol in preventing first variceal hemorrhage 66 ; however, long-term follow-up of patients enrolled in this study showed a higher mortality in a subgroup of patients. 67 ISMN, a potent venodilator, may lead to a higher mortality in these patients by aggravating the vasodilatory state of the cirrhotic patient. 68 In fact, a small trial comparing ISMN to propranolol, besides showing a higher first bleeding rate in the ISMN-treated group, also showed that ISMN led to a significant reduction in sodium excretion. 69 Therefore, the use of nitrates alone should be discouraged.

6 February 2001 MANAGEMENT OF THE COMPLICATIONS OF CIRRHOSIS 731 The combination of a -blocker and ISMN has a synergistic portal pressure reducing effect and could theoretically be more effective than -blockers alone in preventing first variceal hemorrhage. In fact, a nonblinded trial comparing nadolol alone with nadolol plus ISMN demonstrated a significantly lower rate of first hemorrhage in the group treated with combination therapy. 70 These results were maintained after 55 months of follow-up, without differences in survival. 71 However, a larger double-blind placebo-controlled trial was unable to confirm these favorable results. 72 Additionally, combination therapy appears to be associated with more side effects and a higher rate of ascites. 73 Therefore, the use of a combination of a -blocker and ISMN cannot be recommended currently for primary prophylaxis until there is further proof of efficacy. A meta-analysis of prophylactic shunt surgery trials has shown conclusively that, although very effective in preventing first variceal hemorrhage, shunt surgery is accompanied by more frequent encephalopathy and higher mortality rates. 74 Given that the physiology of TIPS is the same as that of surgical shunts (i.e., diversion of blood away from the liver), these results can be extrapolated to TIPS. Therefore, shunt therapy (surgery or TIPS) should be proscribed in the primary prevention of variceal hemorrhage. Despite a large number of studies on prophylactic sclerotherapy, its efficacy in the prevention of first variceal hemorrhage is still uncertain. While early studies showed promising results, latter studies showed a lack of benefit. 74,75 The use of sclerotherapy is therefore not recommended. Because EVL has been shown to be more useful and safe in preventing variceal rebleeding, its usefulness in preventing first hemorrhage has been examined recently. In a trial of 90 patients with large varices that compared EVL with propranolol, the rate of first variceal hemorrhage was significantly lower in the EVL-treated group (9%) than the propranolol-treated group (27%). 76 However, the rate of first hemorrhage in the propranolol-treated group is unusually high and is comparable to the rate of first hemorrhage in placebotreated patients, including placebo-treated patients from a prior study by the same group of investigators. 77 This suggests that patients in the EVL study were not compliant and/or did not receive adequate -blocker therapy. Further studies need to be performed in a larger number of patients before EVL can be widely recommended. In a cost-effectiveness study comparing nonselective -blockers vs. sclerotherapy vs. shunt surgery, -blockers were found to be the only cost-effective form of prophylactic therapy. 78 Recommendation: Nonselective -blockers (propranolol, nadolol, and timolol) are the therapy of choice in patients with medium-sized/large varices that have not yet bled. The dose of -blockers should be adjusted to achieve a 25% reduction in resting heart rate or the maximal tolerable decrease in heart rate to a minimum of 55 beats/min. Propranolol should be administered twice a day; nadolol and timolol can be administered once a day. Once patients are receiving -blockers, follow-up endoscopy is unnecessary. EVL should be contemplated in high-risk patients who have contraindications to -blockers or who have developed severe -blocker related side effects. The use of venodilators should be discouraged because there is as yet no proof of their efficacy and evidence suggests that they could worsen the already altered circulatory state of the cirrhotic patient. In patients with small varices, the risk of hemorrhage is so small that treatment does not seem to be cost-effective. In these patients, follow-up endoscopy should be performed every 1 2 years 8 (Table 1). Treatment of acute variceal hemorrhage. Although bleeding from esophageal varices ceases spontaneously in up to 40% of the patients, the mortality of an episode of variceal hemorrhage is about 30% and occurs mostly in patients with severe liver disease and in those with early rebleeding. Rebleeding occurs in 40% of the patients within 6 weeks. Therefore, in addition to general resuscitative measures, treatment of acute variceal hemorrhage encompasses two important aspects: control of hemorrhage (defined as achieving a 24-hour bleedingfree period within the first 48 hours after starting therapy) and prevention of early recurrence. A general measure that is currently considered standard in the care of patients with variceal hemorrhage is the use of short-term antibiotic prophylaxis. 79 All cirrhotic patients with upper gastrointestinal bleeding, independent of the presence of ascites, are at a high risk of developing severe bacterial infections, and these have been associated to early recurrence of variceal hemorrhage. 80,81 Use of prophylactic antibiotics in cirrhotic patients with gastrointestinal hemorrhage has been shown not only to decrease the rate of bacterial infections but also to increase survival. 82 Therefore, the use of antibiotic prophylaxis in the setting of acute variceal hemorrhage is mandatory. The antibiotic of choice is norfloxacin administered orally at a dose of 400 mg twice a day for 7 days. 79 In most patients, administration by mouth or through a nasogastric tube is possible. In cases in which this is not possible, antibiotics should be administered intravenously. Another general measure that is recommended in the setting of acute variceal hemorrhage is the cautious use of

7 732 GUADALUPE GARCIA TSAO GASTROENTEROLOGY Vol. 120, No. 3 blood products. Because restitution of lost blood has been shown in experimental animals to lead to increases in portal pressure greater than baseline, 83 blood should be replaced to a modest target hematocrit of 25% 30%. Intravascular volume overexpansion should also be avoided because this too can precipitate variceal rebleeding. A recent study in which HVPG measurements were performed within 48 hours from admission for acute variceal hemorrhage showed that an HVPG 20 mm Hg was associated with a high risk of failure to control the acute hemorrhage or of experiencing early rebleeding. 84 Additionally, an HVPG 20 mm Hg was related to a higher 1-year mortality (63% vs. 20%). This study suggests that HVPG monitoring, early in the course of variceal hemorrhage, could be used to select patients who require more aggressive treatment and in the selection of transplant candidates. The advantages of pharmacologic therapy are that it is generally applicable and can be initiated as soon as the diagnosis of variceal hemorrhage is suspected, even before diagnostic endoscopy. This is particularly true for drugs with a good safety profile with which one can afford to misdiagnose a variceal hemorrhage. The most effective and safe drugs are somatostatin and terlipressin, which control acute variceal hemorrhage in 75% 80% of patients. In a trial in which terlipressin plus glyceryl trinitrate (or a double placebo) were administered early on, even before hospitalization, control of variceal hemorrhage was significantly better and bleeding-related mortality was significantly lower in the treatment group. 85 Unfortunately, neither somatostatin nor terlipressin are available in the United States. However, vasopressin and the somatostatin analogue octreotide are available in the United States. The use of vasopressin is limited by the presence of side effects. Its efficacy and safety are significantly improved by the addition of nitrates; nevertheless, side effects of combination therapy are still higher than those associated with terlipressin or somatostatin. 63 Vasopressin is administered at a continuous infusion of U/min, dose that can be increased to a maximum of 0.8 U/min. It should always be accompanied by intravenous nitroglycerin at a starting dose of 40 g/min that can be increased to a maximum of 400 g/min, adjusted to maintain a systolic blood pressure 90 mm Hg. Continuous infusion of vasopressin/nitroglycerin cannot be recommended for more than 24 hours because of an increased incidence of adverse effects. In terms of the somatostatin analogue octreotide, a recent meta-analysis suggests that it has no or little effect when used alone. 63 Endoscopic sclerotherapy has been shown to be highly effective both in controlling active hemorrhage and in preventing early rebleeding and has become the gold standard in the management of acute variceal hemorrhage. 74 Emergency sclerotherapy stops bleeding in about 80% 90% of patients. According to a recent meta-analysis, 86 sclerotherapy and EVL appear to be equally effective in the emergency situation. A study that specifically addressed the control of acute variceal hemorrhage showed, however, that EVL was associated with a greater efficacy and a lower number of complications than sclerotherapy. 87 Sclerotherapy is not optimal for patients bleeding from gastric fundal varices, and there is some evidence suggesting that acrylate glue injection is more effective than ethanolamine oleate. 88 The role of glue and EVL in the control of bleeding from fundal varices remains to be determined. The use of somatostatin or analogues as adjuncts to endoscopic therapy appears to be the most promising approach in the treatment of acute variceal hemorrhage. Given the lack of side effects, their use can be extended to 5 days, the period during which the risk of rebleeding is the highest. In this way, rather than controlling the acute episode (which will be achieved by endoscopic therapy), the goal of somatostatin or somatostatin analogues would be the prevention of early rebleeding. In a placebo-controlled trial of 5-day infusion of somatostatin as adjuvant to sclerotherapy, failure of therapy was significantly lower in the group that received somatostatin (35%) than in the placebo-treated group (55%). 89 Octreotide and other somatostatin analogues may improve the outcome of endoscopic therapy, although results from placebo-controlled trials remain controversial. One such study showed a benefit of octreotide as an adjuvant to sclerotherapy, 90 but others have been unable to demonstrate a benefit of adding octreotide to sclerotherapy 91 or to standard local practice. 92 The recently described rapid desensitization to the effects of octreotide may explain these divergences. 49 Results of ongoing large trials of another somatostatin analogue, lanreotide, should be helpful in clarifying this issue. Despite urgent sclerotherapy and/or pharmacologic therapy, bleeding cannot be controlled or has an early recurrence in about 10% 20% of patients. Shunt therapy, either shunt surgery (in Child A patients) or TIPS, is of proven clinical efficacy as salvage therapy for patients who do not respond to endoscopic or pharmacologic therapy. 93,94 Although it has been suggested that bleeding from gastric varices is more difficult to control with TIPS than bleeding from esophageal varices, a

8 February 2001 MANAGEMENT OF THE COMPLICATIONS OF CIRRHOSIS 733 recent study showed equal effectiveness of TIPS in both situations. 95 Recommendation: Endoscopic therapy (either sclerotherapy or EVL) is the therapy of choice in the management of acute variceal hemorrhage. The association of pharmacologic therapy, used as soon as the diagnosis is suspected (even before endoscopy) and continued for 5 days after the diagnosis is established, may represent the best approach to treatment. Shunt surgery or TIPS is indicated in patients in whom hemorrhage from esophageal varices cannot be controlled or in whom bleeding recurs despite two sessions of endoscopic therapy (associated or not with pharmacologic therapy). In patients who bleed from fundal varices, failure of one sclerotherapy session should be enough to indicate the performance of shunt therapy. Balloon tamponade is very effective in controlling bleeding temporarily; however, its use is associated with potentially lethal complications and should be limited to patients with uncontrollable bleeding in whom a more definitive therapy (e.g., TIPS) is being planned (Table 1). Prevention of recurrent variceal hemorrhage. Variceal hemorrhage has a 2-year recurrence rate of approximately 80%. It is therefore indispensable that patients who survive an episode of variceal hemorrhage be started on therapy to prevent recurrence before discharge from hospital. Both pharmacologic therapy with nonselective blockers and sclerotherapy have been shown to reduce variceal rebleeding and death compared with untreated controls. In these studies, rebleeding rates of 57% 63% are described in untreated controls compared with rates of 42% 43% in treated patients. 63,74,86 A meta-analysis of 10 randomized trials comparing propranolol with sclerotherapy in the prevention of variceal rebleeding shows comparable rates of variceal rebleeding and survival for both therapies, with a significantly higher rate of side effects with sclerotherapy. 63 Therefore, treatment with -blockers is preferable to sclerotherapy in the prevention of rebleeding. The combination of -blockers and ISMN has been shown to be superior to -blockers alone 96 and to sclerotherapy 97 in the prevention of variceal rebleeding. However, a deleterious effect of combination therapy on survival was recently described in a placebo-controlled trial that compared nadolol plus placebo vs. nadolol plus ISMN. 98 Therefore, combination therapy cannot be fully recommended until this issue is clarified. Compared with sclerotherapy, EVL has been shown to be associated with lower rebleeding rates, a lower frequency of esophageal strictures, and the need for fewer sessions to achieve variceal obliteration. 86,99 Therefore, EVL is considered the endoscopic treatment of choice in the prevention of variceal rebleeding. EVL sessions are repeated at 7 14-day intervals until variceal obliteration, which usually requires 2 4 sessions. 99 It has been suggested that varices recur more frequently after EVL than after sclerotherapy, but this could not be demonstrated by meta-analysis. 86 Two recent studies published in abstract form suggest that combination pharmacologic therapy ( -blocker plus nitrates) is at least as effective as EVL in preventing variceal rebleeding. 100,101 Combining endoscopic therapy with pharmacologic therapy is rational because -blockers will theoretically protect against rebleeding in the period before variceal obliteration and would prevent variceal recurrence. A recent randomized trial showed that the combination of EVL plus nadolol plus sucralfate is more effective in preventing variceal rebleeding than EVL alone, 102 with rebleeding rates of 23% and 47%, respectively. Currently, it would seem reasonable to combine -blockers with EVL in cases in which pharmacologic therapy has failed. Shunt surgery is very effective in preventing rebleeding; however, it markedly increases the risk of portosystemic encephalopathy, without an effect on survival. 74,103 Not surprisingly, recent meta-analyses of 11 trials that compared TIPS with endoscopic therapy show similar results. 104,105 That is, although rebleeding is significantly less frequent with TIPS, posttreatment encephalopathy occurs significantly more often after TIPS without differences in mortality. Additionally, shunt dysfunction occurs quite frequently, with 77% of patients requiring balloon angioplasty or restenting in the first year. 7 Because of these limitations, the recommended use of TIPS (and shunt surgery) is restricted to a tertiary position in the prevention of variceal rebleeding. Recommendation: Pharmacologic therapy with -blockers and EVL are accepted therapies in the prevention of variceal rebleeding. The choice will depend on factors such as expertise, compliance, tolerance, and patient preference. The combination of EVL and pharmacologic therapy should be considered in patients who rebleed during -blocker treatment or on EVL. Patients who rebleed during combined pharmacologic/endoscopic therapy should be considered for shunt therapy, either surgical or TIPS (Table 1). Ascites Ascites is one of the most frequent complications of cirrhosis. In compensated cirrhotic patients, ascites develops at a 5-year cumulative rate of about 30%. 106 Once ascites develops, 1-year survival is about 50%

9 734 GUADALUPE GARCIA TSAO GASTROENTEROLOGY Vol. 120, No. 3 compared with a 1-year survival of 90% in patients with compensated cirrhosis Prognosis is particularly poor in patients who develop refractory ascites 110 or hepatorenal syndrome (HRS). 111 Treatment of ascites has not resulted in significant improvements in survival. However, treating ascites is important, not only because it improves the quality of life of cirrhotic patients but because spontaneous bacterial peritonitis (SBP), one of the most lethal complications of cirrhosis, does not occur in the absence of ascites. The development of ascites in cirrhotic patients is an indication for liver transplantation, and transplantation constitutes the ultimate treatment for ascites and its complications. As mentioned above and as shown in Figures 1 and 3, ascites results from sinusoidal hypertension and sodium retention. In the great majority of patients with ascites, sodium retention results from peripheral vasodilatation that leads to a decrease in effective arterial volume and activation of sodium-retaining humoral systems. 9 Rationale for the Different Therapeutic Maneuvers The different treatment options for ascites, placed in the context of its pathogenesis, are depicted in Figure 3. Attaining a negative sodium balance. Given that sodium retention is one of the main mechanisms in the development of ascites, a central goal of therapy is the attainment of a negative sodium balance. To achieve a negative sodium balance, sodium output must exceed its input. Sodium restriction is the simplest measure that can be used in the treatment of ascites. A low-salt diet and bed Figure 3. Treatment options for ascites placed in the context of its pathogenesis. rest will eliminate ascites in 10% 20% of patients. 112,113 These patients can be identified by a relatively high baseline urinary sodium excretion ( 50 meq/day) and by the presence of a small to moderate amount of ascites. No complications are associated with dietary sodium restriction other than the potential of impairing the nutritional status of the cirrhotic patient because of nonpalatability of the diet. Diuretics are required in most patients with ascites, particularly in those with moderate-to-tense ascites, who retain sodium avidly and in whom sodium restriction will not be sufficient to obtain a negative sodium balance. Sodium retention in cirrhosis is mainly the result of increased distal tubular reabsorption of sodium; therefore, distal diuretics such as spironolactone should be the diuretics of choice. In fact, two randomized trials have shown a significantly lower efficacy of the loop diuretic furosemide used alone compared with spironolactone alone 114,115 or with the combination of spironolactone and furosemide. 114 When furosemide is used alone, sodium that is not reabsorbed in the loop of Henle is taken up at the distal and collecting tubules as a result of the hyperaldosteronism present in most cirrhotic patients with ascites. Therefore, furosemide should not be used as the sole agent in the treatment of cirrhotic ascites. Treatment with diuretics is associated with a high incidence of complications. The more commonly described complications are renal impairment caused by intravascular volume depletion (25%), hyponatremia (28%), and hepatic encephalopathy (26%) Spironolactone is often associated with adverse events related to its antiandrogenic activity, mainly painful gynecomastia. Potassium canrenoate, one of the major metabolites of spironolactone, has a comparable diuretic effect and a lower antiandrogenic activity and could be used in these cases, 119,120 but this drug is not available in the United States. Amiloride, another potassium-sparing diuretic, does not produce gynecomastia but it has significantly less natriuretic effect than spironolactone. 121 A recent double-blind crossover study suggests that the estrogen antagonist tamoxifen at a dose of 20 mg twice a day may be useful in the management of painful gynecomastia in cirrhotic patients. 122 Removing intraperitoneal fluid and expanding the intravascular volume. The oldest therapy for ascites consists of extracting fluid from the abdomen through a needle. Large-volume paracentesis (LVP) was the treatment of choice for cirrhotic ascites until the 1950s, when it went into disuse because diuretics became available and because of anecdotal reports of hypotension and renal failure leading to death in some patients. In the mid-

10 February 2001 MANAGEMENT OF THE COMPLICATIONS OF CIRRHOSIS s, it was demonstrated that (5-L) LVP had no deleterious effects on systemic hemodynamics or on renal function. 123 A landmark clinical trial comparing LVP with standard therapy with diuretics showed that LVP (daily extraction of 5 L, associated with intravenous albumin) resulted in a faster resolution of ascites and a significantly lower rate of complications. 116 Subsequent trials confirmed these results and established the safety of single, total paracentesis (associated with intravenous albumin). 117,124 The low rate of complications related to LVP has been demonstrated in more than 400 patients collected in trials comparing LVP with diuretics or other therapies for ascites, with renal dysfunction occurring in only 3% of the cases and hyponatremia and encephalopathy in 8% each , Concomitant plasma volume expansion with either albumin or synthetic expanders (hemaccel, dextran-70, or dextran-40) has been used with LVP in all the abovementioned trials. Albumin is used in patients with cirrhosis and ascites with the objective of increasing intravascular oncotic pressure, but its main effect lies in correcting the decreased effective arterial volume that leads to sodium retention. 131 A trial comparing daily LVP with and without intravenous albumin infusion showed that, although these treatments were equally effective, the group treated without concomitant albumin infusion had a significantly higher incidence of hyponatremia and renal impairment. 125 Marked elevations in plasma renin activity and plasma aldosterone concentrations were also noted, indicating that LVP without albumin was associated with a (further) decrease in effective arterial volume ( postparacentesis circulatory dysfunction ) and suggested that plasma expansion should always accompany LVP. Although albumin is costly and its availability is limited, it is the plasma expander of choice. In a large multicenter trial, albumin was shown to be associated with a lower incidence of postparacentesis circulatory dysfunction (PCD) (18%) compared with synthetic plasma expanders (38% for polygeline and 34% for dextran-70). 129 PCD has been defined as an increase in plasma renin activity on the sixth day after paracentesis (indicative of a decreased effective arterial blood volume) and is not spontaneously reversible. 129 Patients who develop PCD have a faster reaccumulation of ascites and a significantly shorter median survival time than patients who do not develop PCD (10 vs. 7 months). A hemodynamic study showed that patients who develop PCD have a significantly greater reduction in mean arterial pressure and in systemic vascular resistance after paracentesis than patients who do not develop PCD. 132 This study also showed that changes in renin correlate inversely with changes in systemic vascular resistance, suggesting that, in cirrhotic patients who develop PCD, total paracentesis leads to further vasodilatation and hypovolemia, through mechanisms that are as yet undetermined. The type of plasma expander and the volume of ascites removed are the only independent predictors of PCD. 129 When the volume of ascites removed is 5 L, a similar incidence of PCD is observed in albumin-treated patients and those treated with a synthetic plasma expander. However, with volumes 5 L, the incidence of PCD increases significantly only in patients treated with dextran-70 or polygeline but not in those treated with albumin. It is probable that albumin is able to better correct the relative hypovolemia that occurs after paracentesis given its greater oncotic potency and longer half-life. A therapy that combines removal of intraperitoneal fluid and replenishment of the intravascular volume is the peritoneovenous shunt (PVS). It consists of a silicone tube system with a distal fenestrated limb that is placed in the peritoneal cavity and is connected through a one-way pressure-sensitive valve to a tube that is tunneled under the skin and placed into the right atrium. In PVS, ascites and its components act as the plasma volume expander. The shunt can be placed under local anesthesia and has been shown to eliminate ascites, increase diuresis and the response to diuretics, and to markedly suppress renin, aldosterone, norepinephrine, and antidiuretic hormone, indicative of an improvement in the circulatory state. Unfortunately, PVS becomes obstructed at a high rate (50% in the first year). Obstruction is usually caused by deposition of fibrin within the valve or to thrombotic obstruction of the venous limb, but could not be prevented with the use of a titanium tip at the venous end of the shunt. 133 Additionally, PVS can lead to potentially lethal complications such as infection, disseminated intravascular coagulation, precipitation of variceal hemorrhage or heart failure, and intestinal obstruction. 134,135 Relieving sinusoidal hypertension and expanding the intravascular volume. Because sinusoidal hypertension is an important factor in the pathogenesis of ascites, treatment of ascites has also been aimed at reducing sinusoidal pressure. The side-to-side portocaval shunt, by decompressing both the portal and sinusoidal beds, decreases hepatic and splanchnic lymph formation. Surgical reduction of portal pressure by portosystemic shunting is accompanied by an increase in urinary excretion of sodium and a decrease or normalization of antinatriuretic systems, suggesting an improvement in circulatory state.