Use of Diuretics in Heart Failure and Cirrhosis

Robert W. Schrier, MD
Summary: Sodium and water retention in cardiac failure and cirrhosis is pivotal in the morbidity and mortality of patients with these disorders. Moreover, the pathophysiology of these edematous disorders is quite similar. Both disorders have activation of the renin-angiotensin-aldosterone system, increased sympathetic activity, and nonosmotic stimulation of arginine vasopressin, which is initiated by unloading of the arterial baroreceptors; this occurs secondary to diminished cardiac output with heart failure and primary systemic arterial vasodilation with cirrhosis. With this common pathophysiology causing pulmonary congestion, ascites, and peripheral edema, diuretics are pivotal in the therapy of patients with heart failure and cirrhosis. Advanced cardiac failure and cirrhosis both show secondary hyperaldosteronism and impaired renal escape from the sodium-retaining effect of aldosterone. However, currently there are contradictory uses of mineralocorticoid-receptor antagonists in cardiac failure (non-natriuretic doses) versus cirrhosis (natriuretic doses). This disparity relates to the greater potential of hyperkalemia in cardiac failure patients receiving inhibitors of the renin-angiotensin-aldosterone system. This review discusses the benecial and potentially deleterious effects of diuretic use in patients with cardiac failure and cirrhosis. Semin Nephrol 31:503-512 2011 Elsevier Inc. All rights reserved. Keywords: Edema, ascites, secondary hyperaldosteronism

he appropriate use of diuretics in patients with cardiac failure and cirrhosis necessitates an understanding of the pathophysiology of these edematous disorders. Patients with advanced heart or liver disease not only have expansion of extracellular uid volume (ECFV), but also total blood volume. Such volume expansion in normal individuals would lead to increased urinary sodium excretion, yet these edematous patients have avid renal sodium retention. This apparent dilemma indicates that the sodium and water retention by the kidney in heart and liver failure is not responding to either expansion of ECFV or blood volume. The kidney does not appear to be the primary culprit, however, because after a successful heart or liver transplant there is no longer renal sodium retention. The atrial-renal reexes also do not appear to be intact in these major edematous disorders. For example, an increase in atrial pressure has been shown to suppress the release of vasopressin and lead to a water diuresis.1 Moreover, atrial natriuretic peptide hormone is released during an increase in atrial pressure and leads to a natriuresis.2 Furthermore, an increase in atrial pressure has been found to decrease renal vascular resistance.3 Although these atrial-renal reexes in the low-pressure, venous side of the circulation occur in normal circumstances, they are not evident in cardiac failure and cirDivision of Renal Diseases and Hypertension, University of Colorado Denver School of Medicine, Aurora, CO. Address reprint requests to Robert W. Schrier, MD, Professor of Medicine, Division of Renal Diseases and Hypertension, University of Colorado, 12700 East 19th Ave C281, Research 2, Room 7001, Aurora, CO 80045. E-mail: robert.schrier@ucdenver.edu 0270-9295/ - see front matter 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2011.09.005

rhosis. Specically, in patients with advanced cardiac failure atrial pressure increases and yet renal sodium and water retention is occurring. Plasma atrial natriuretic peptide increases in both heart failure and cirrhosis, yet the kidney is retaining sodium.4 On this background the modulation of renal sodium and water retention in cardiac failure and cirrhosis has focused on the estimated 15% of the total blood volume that resides in the arterial portion of the circulation; the remaining 85% of blood volume is on the venous, lowpressure side of the circulation. The arterial circulatory integrity is served by arterial baroreceptors that are located in the carotid sinus, aortic arch, and glomerular afferent arteriole. Under normal circumstances there is tonic inhibition of sympathetic efferent activity from the central nervous system via the glossopharyngeal and vagus nerves from the arterial baroreceptors. Unloading of this tonic inhibition on these stretch receptors leads to activation of the neurohumoral axis including increased activity of the sympathetic and renin-angiotensin-aldosterone systems (RAAS), as well as the nonosmotic release of arginine vasopressin (AVP). With low-output cardiac failure this arterial underlling and activation of the neurohumoral axis is caused by a decrease in cardiac output (Fig. 1).5 With cirrhosis, splanchnic vasodilation causes primary systemic arterial vasodilation leading to unloading of arterial baroreceptors with resultant activation of the neurohumoral axis (Fig. 2).5 High-output failure (eg, beriberi, thyrotoxicosis) also appears to cause arterial underlling by primary systemic arterial vasodilation with a secondary increase in cardiac output, as occurs in cirrhosis. Although activation of the neurohumoral axis in states of arterial underlling maintains arterial perfusion to several vital organs, the kidney undergoes vasoconstric503

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Figure 1. Decrease in cardiac output causes arterial underlling with resultant neurohumoral activation and renal sodium and water retention. Reprinted with permission from Bansal et al.5

tion and begins retaining sodium and water. The increased tubular sodium reabsorption is mediated, at least in part, by angiotensin and adrenergic receptors.6 Moreover, as renal arterial pressure declines with advanced cardiac or liver failure, further enhancement of tubular sodium reabsorption occurs.7 These events lead to diminished delivery of sodium chloride to the mineralocorti-

coid receptor sites in the collecting duct, which results in failure of the normal aldosterone escape mechanism (Fig. 3).8 Thus, the sodium-retaining effect of the secondary hyperaldosteronism in advanced cardiac failure and cirrhosis persists. Moreover, baroreceptor-mediated nonosmotic release of AVP occurs in both cardiac9 and liver failure.10 This overrides the osmotic regulation of AVP

Figure 2. Primary systemic arterial vasodilation causes arterial underlling with resultant neurohumoral activation and renal sodium and water retention. Reprinted with permission from Bansal et al.5

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Figure 3. Role of diminished distal sodium delivery to impair aldosterone escape in states of arterial underlling including cardiac failure and cirrhosis. Reprinted with permission from Schrier and Better.8

and leads to hyponatremia in association with increased thirst that also occurs secondary to the arterial underlling in these edematous disorders. On this pathophysiological background the use of diuretics in cardiac failure and cirrhosis can be discussed more easily.

DIURETIC USE IN CARDIAC FAILURE

Heart failure is the cause of approximately 1 million hospitalizations each year in the United States and is increasing in parallel with the aging population.11 Approximately 50% of patients admitted for cardiac decompensation are discharged with persistent symptoms.12 Results from the Acute Heart Failure Registry (ADHERE) in 105,388 hospitalized patients showed that 33% were discharged with a loss in body weight of 5 pounds or less and 16% were discharged with increased body weight. Ninety percent were on intravenous loop diuretics and 30% were considered to be diuretic resistant.12 Rehospitalization during the 60 to 90 days after discharge was reported to approach 25% of heart failure patients.13 Even before signs and symptoms of systemic and pulmonary congestion occur, increased left ventricular lling pressures generally are present. This has been termed hemodynamic congestion in heart failure,14 a predecessor to clinical congestion. This increased ventricular lling pressure may lead to worsening cardiac function secondary to subendomyocardial ischemia, increased ventricular wall stress, secondary mitral insufciency, and impaired cardiac venous drainage, which combined can lead to diastolic dysfunction. A considerable percentage of heart failure patients are admitted to the hospital with a normal

cardiac ejection fraction. However, as shown in Fig. 4, any normalization of cardiac index as well as the neurohumoral axis in these heart failure patients is at the expense of increased ECFV and the resultant deleterious effects of increased ventricular lling pressures.15 From the ADHERE database the signs and symptoms of patients hospitalized for heart failure were dyspnea (89%), pulmonary rales (67%), and peripheral edema (66%).13 The benecial effects of loop diuretics on these symptoms and signs are well established. Moreover, with advanced pulmonary edema hypoxia, hypercapnea and metabolic acidosis may occur and contribute to depressed cardiac function. These abnormalities can be improved with loop diureticinduced urinary sodium and water losses. Moreover, the diuretic-induced negative sodium and water balance can decrease cardiac dilatation, functional mitral insufciency, and decrease ventricular wall stress and endomyocardial ischemia (Fig. 5).15 However, there are potential negative effects of loop diuretic use in heart failure patients. Treatment of heart failure patients with loop diuretics may be associated with deterioration of renal function and even mild renal dysfunction has been associated with increased cardiovascular mortality.16 The question then emerges whether these patients need to remain in a volume overload state to maximize their cardiac index on the Frank-Starling curve and thereby avoid deterioration of renal function. Another dilemma with loop diuretics is their inhibition of sodium chloride uptake at the macula densa, which results in further stimulation of the RAAS independent of any further negative sodium and water balance. Because

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Figure 4. Feedback mechanisms for normalizing neurohormones and cardiac index with myocardial injury. Myocardial injury can lead to sodium and water retention, which can suppress the RAAS and return cardiac index to a normal range. The dashed lines indicate the pathways of these feedback mechanisms. To exclude myocardial injury when these feedback mechanisms have normalized the RAAS and cardiac index would be a mistake. Reprinted with permission from Schrier.15

both angiotensin and aldosterone have been shown to contribute to cardiac remodeling and brosis, this secondary effect of loop diuretics on the RAAS may be deleterious.17 The Randomized Aldosterone Evaluation Study (RALES) in patients with severe heart failure showed that a mean spironolactone dose of 26 mg/d led to a 30% decrease in all-cause and cardiovascular mortality.18 An earlier dosending study by the RALES group showed that in these patients with severe heart failure 25 mg/d of spironolactone did not alter urinary sodium excretion.19 The results were therefore determined to occur by the mineralocorticoid-

receptor antagonist blocking the brotic and oxidant injury mediated by aldosterone on the heart.18 In the Eplerenone Post-AMI Heart Failure Efcacy and Survival Study (EPHESUS), administration of another mineralocorticoidreceptor antagonist, eplerenone (50 mg/d), in patients with an acute myocardial infarction and heart failure was reported to improve survival.20 Although sodium balance was not reported in EPHESUS, 50 mg of eplerenone equates to 25 mg of spironolactone on urinary sodium excretion. These results therefore also were considered to be caused by blocking the non-natriuretic, nongenomic effects of aldosterone on the heart.20

Figure 5. Mechanisms in congestive heart failure whereby negative sodium and water balance by loop diuretics may improve myocardial function. Reprinted with permission from Schrier.15

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Figure 6. Mechanisms of diuretic resistance with potential benet of mineralocorticoid antagonism. Dotted line indicates inhibition. Reprinted with permission from Bansal et al.5

Another consequence of further stimulation of the RAAS by loop diuretics in heart failure with hemodynamic or clinical congestion is diuretic resistance. Diuretic resistance is associated with up-regulation of the renal NaCl cotransporter and hypertrophy in the distal nephron. Also, the decreased sodium ltration rate and enhanced sodium chloride reabsorption in the proximal tubule results in diminished NaCl delivery to the ascending limb of Henle, the site of action of loop diuretics. There is evidence that the up-regulation of the NaCl cotransporter with diuretic resistance is at least partially caused by aldosterone.21 The effect of secondary hyperaldosteronism on the distal collecting duct in advanced heart failure also may attenuate any loop diuretic effect at the earlier ascending limb site in the nephron (Fig. 6).5 Thus, the use of adequate doses of mineralocorticoidreceptor antagonists to compete with the increased endogenous levels of aldosterone may attenuate the diuretic resistance observed in severe heart failure. Thiazide diuretics that act on the NaCl cotransporter in the distal tubule also can be added to loop diuretics to counteract diuretic resistance. Metolazone has a long duration of action, therefore, the side effect of hypokalemia when added to loop diuretics may exceed that of a shorteracting thiazide diuretic. There are some results that indicate that uid mobilization from the interstitium into the intravascular compartment is limited to 12 to 14 mL/min in patients with

heart failure.22 Thus, a more vigorous diuresis with loop diuretics may lead to diminished intravascular volume and worsening of arterial underlling, with resultant further deterioration of cardiac and renal function. Diuresis with loop diuretics therefore must be undertaken carefully and an initial increase in blood urea nitrogen and serum creatinine levels may not be the basis for ceasing diuretic therapy, but rather a signal to be more judicious. There are other issues regarding the use of loop diuretics in patients with severe heart failure. Frequently, heart failure patients are observed receiving once-a-day furosemide and are termed diuretic resistant. This is inappropriate because furosemide lasts only 6 hours and therefore the kidney continues to avidly retain sodium during the remaining 18 hours of the day. Furosemide therefore should be administered at least twice a day. Continuous intravenous infusion of furosemide can be used, however, the results suggesting a benet compared with bolus therapy is tenuous. In patients with renal impairment intravenous bolus therapy with furosemide should be given over 20 to 30 minutes to avoid ototoxicity. The administration of loop diuretics may lead to hypokalemia, hypomagnesemia, and hypocalemia, all of which can predispose heart failure patients to serious arrhythmias, particularly those receiving digoxin.23 Loop diureticinduced hypokalemic metabolic alkalosis with high serum bicarbonate also may predispose to cardiac arrhythmias. In the presence of cardiac failure the stan-

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Figure 7. Reversal of sodium retention with aldosterone antagonism in patients with heart failure. Left: positive sodium balance without spironolactone. Right: negative sodium balance with spironolactone. Reprinted with permission from Hensen et al.29

dard treatment of metabolic alkalosis with ECFV volume expansion is contraindicated. However, use of a carbonic anhydrase inhibitor may cause bicarbonaturia and can be given after potassium replacement to correct metabolic alkalosis in patients with severe heart failure. Currently in the United States the use of mineralocorticoid-receptor antagonists in severe heart failure has been largely restricted to the nongenomic, non-natriuretic doses of spironolactone (25 mg/d) and eplerenone (50 mg/d). The reason for this probably relates to the fear of hyperkalemia.24 Only minor (0.3-0.4 mEq/L) increases in serum potassium concentration were observed in the RALES and EPHESUS studies. However, one observational study in the New England Journal of Medicine from Canada reported a temporal increase in spironolactone prescriptions as well as an increase in hospital admissions and in-hospital deaths temporally associated with the RALES report.25 This observational study analyzed International Classications of Diseases, 9th edition codes of hospitalized patients, which generally denes hyperkalemia by a blood potassium concentration greater than 5.0 mEq/L. The potassium concentration also was only one of many associations for hospitalizations and in-hospital deaths. A recent study from Scotland26 using a record linkage database examined all patients receiving one or more prescriptions for spironolactone between 1994 and 2007. Despite a large increase in use of spironolactone in patients with and without heart failure, there was no increase in hospitalization for hyperkalemia. Hyperkalemia, however, was dened as a serum potassium level greater than 6.0 mEq/L. Although there are little data published on the use of natriuretic doses of spironolactone in patients with severe heart failure, there have been some small reports. In 1961 Braunwald et al27 showed a natriuretic response to 100 mg of spironolactone in three patients with heart disease. Another study in heart failure patients with diuretic resistance who were on an angiotensin-converting enzyme (ACE) inhibitor showed a natriuretic response to 100 mg of spironolactone without a clinically important increase in serum potassium concentration.28 In another study all medications were stopped for 3 days in patients with

severe heart failure and a substantial positive sodium balance occurred. Treatment with oral spironolactone 200 mg twice a day returned these patients to normal sodium balance over the next 4 days without a clinically signicant increase in serum potassium concentration (Fig. 7).29 Given the suboptimal response of heart failure patients hospitalized for clinical congestion as reported by the ADHERE study,12,13 an investigation of mineralocorticoid-receptor antagonist titrated to natriuretic doses with close monitoring of serum potassium concentration needs to be undertaken. This careful monitoring is particularly true in hospitalized patients with heart failure who are receiving -blockers, ACE inhibitors, and/or angiotensin receptor blockers.24 These patients should be on a potassium-restricted diet, remembering that sodiumrestricted diets may have potassium-containing salt substitutes. Potassium supplements should be avoided and, where appropriate, potassium-losing loop diuretics will help to avoid hyperkalemia when administering mineralocorticoid-receptor antagonists along with drugs that inhibit the RAAS. Nonsteroidal anti-inammatory agents, potassium-sparing diuretics, and heparin also may predispose to hyperkalemia. Finally, the water retention and hyponatremia with advanced heart failure may be treated with uid restriction, but the response is slow and may not be tolerated. There are now two Food and Drug Administrationapproved V2 receptor antagonists available that can be used in heart failure to increase electrolyte-free water excretion and correct hyponatremia. Conivaptan is a combined V2, V1-receptor antagonist that can be used parenterally for 4 days in-hospital to correct hyponatremia.30 Tolvaptan is an orally active, selective V2-receptor antagonist that must be started for the rst day of administration in-hospital with careful monitoring of serum sodium concentration every 6 to 8 hours.31 With the use of either V2-antagonist agent in heart failure patients with chronic hyponatremia the increase in plasma sodium concentration should not exceed 10-12 mEq/L in 24 hours or 18 mEq/L in 48 hours. After the rst day tolvaptan can be used in the outpatient setting. A recent publication showed a sustaining effect in correcting hyponatremia for

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Figure 8. Peripheral systemic arterial vasodilation hypothesis. NE, norepinephrine. Reprinted with permission from Schrier et al.36

as long as 2 years.32 The side effects of these aquaretic agents primarily relate to their physiological action to increase urination and thirst.

USE OF DIURETICS IN CIRRHOTIC PATIENTS

The Underll hypothesis was based on ascites formation leading to a decrease in blood volume with resultant renal sodium and water retention. The Overow hypothesis emerged once measurements of blood volumes in cirrhotic patients were shown to be increased rather than decreased. The Overow hypothesis proposed that a hepatic-renal reex existed that caused sodium retention, blood volume expansion, and ascites formation. However, as cirrhotic patients progressed from compensated (no ascites) to decompensated (ascites) to hepatorenal syndrome (HRS), the cirrhotic patients had a progressive increase in the stimulation of the neurohumoral axis. This did not seem to be compatible with progressive volume expansion, particularly of the arterial circulation. In fact, because the RAAS and sympathetic systems progressively are stimulated along this spectrum of liver disease toward the HRS, there is a strong correlation with the increased levels of plasma renin activity and norepinephine33,34 with mortality. Moreover, pretreatment hyponatremia in cirrhosis is a strong prediction of progression to HRS and increased mortality.35 On this background the Primary Systemic Arterial Vasodilation hypothesis emerged and has in general been accepted to better explain the spectrum of cirrhotic disease than either the Underll or Overow hypotheses (Fig. 8).36 Nonselective inhibition of nitric oxide synthase with a dose that reverses the vasodilated hyperdynamic circulation in experimental cirrhosis was shown to be associated with suppression of plasma AVP and aldosterone with a

loss of ascites over 7 days in a majority of cirrhotic animals.37 This approach, however, has not yet been translated to cirrhotic patients. The earliest studies primarily used loop diuretics to treat cirrhotic patients with ascites. Estimates of uid mobilization with diuretics suggested that a maximum of 1 L/d of ascites could be mobilized without substantial complications such as decreasing renal function. Furthermore, there were even recommendations that ascitic cirrhotic patients should not be diuresed at all because of the potential deterioration of kidney function that correlates with mortality. A randomized study, however, showed that more gradual diuresis with natriuretic doses of spironolactone could achieve disappearance of ascites over 3 to 4 weeks without complications as compared with placebo (Table 1).38 Thus, inhibition of the secondary hyperaldosteronism with adequate doses of mineralocorticoid-receptor antagonists has emerged as the primary diuretic therapy in cirrhotic patients with ascites. In fact, the International Ascites Club recommends not declaring diuretic resistance in cirrhotic patients until they are not responding to 400 mg of spironolactone and 160 mg of furosemide.39

Table 1. Aldosterone Antagonism Promotes Weight Loss and Disappearance of Ascites in Decompensated Cirrhosis
Cirrhotic Patients Parameter Control (n 22) Spironolactone (n 21)

Death Weight loss, lb Disappearance of ascites

7 6 4 2

5 24 4 16

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Figure 9. Double-blind, placebo-controlled study of lixivaptan in hyponatremic cirrhotic patients showing urinary osmolality (left) and serum sodium (right). Reprinted with permission from Gerbes et al.42

The side effects with spironolactone include breast pain, gynecomastia, and impaired sexual performance. Because the mineralocorticoid-receptor antagonist eplerenone does not block progesterone and androgen receptors, these side effects are less evident. Cirrhotic patients generally do not receive either ACE inhibitors or angiotensin-receptor blockers and in fact inhibition of the RAAS system may be associated with hypotension. Hyperkalemia in cirrhotic patients receiving mineralocorticoid antagonists therefore appears to be less of a potential problem than with heart failure patients. However, cirrhotic patients may be receiving doses of nonspecic -blockers (eg, propranolol, atenolol) to treat portal hypertension. These agents suppress the RAAS and therefore may increase the risk of hyperkalemia when administered with mineralocorticoid-receptor antagonists. Because the effect of aldosterone on sodium transport involves increased synthesis of the epithelial sodium channel, blockade of the epithelial sodium channel with amiloride also can be effective as a diuretic in treating cirrhotic patients with ascites. Again, a potential side effect is hyperkalemia, which, when accompanied by a potassium-losing loop diuretic, is generally not a problem. Prospective studies have shown that an important adjunct to diuretic therapy is abdominal paracentesis.39 With replacement of 8 g of albumin per liter of ascites removed by paracentesis, hemodynamic stability can be maintained without complications. A comparison of ab-

dominal paracentesis with removal of maximal ascites at one sitting versus over several days showed no clinical differences as long as albumin was replaced.40 Randomized studies have shown that abdominal paracentesis compared with diuretic treatment decreases the number of hospitalizations but does not affect survival. Continued diuretic treatment, however, must accompany the intermittent paracentesis in treating cirrhotic patients with ascites. The occurrence of diuretic resistance with a maximal dose of mineralocorticoid antagonists, even before occurrence of HRS, is of clinical importance. Specically, when there is no evidence of reversible liver disease, for example, alcoholic or acetaminophen hepatitis, and abstinence of alcohol for at least 6 months, it is recommended to place these cirrhotic patients on the liver transplant list before they develop HRS. This is because the outcomes for liver transplants have been found to be worse once the patient has developed HRS.41 With the arterial underlling secondary to systemic arterial vasodilation in cirrhotic patients, nonosmotic stimulation of AVP and thirst occur and override the effect of hypo-osmolality to suppress AVP and thirst. The resultant hyponatremia is a powerful risk factor for developing HRS and mortality.35 V2-receptor antagonists have been used to treat hyponatremic cirrhotic patients.

Table 3. Types of HRS Type 1 Rapidly progressive Serum creatinine level double to 2.5 mg/dL or creatinine clearance 20 mL/min in 2 weeks Prognosis: 80% die in 2 weeks Frequently precipitating events (eg, spontaneous bacterial peritonitis) Type II Slower deterioration Serum creatinine level 1.5 mg/dL or creatinine clearance mL/min but decline is slow Most patients die within several weeks Most frequent cause of therapy-resistant ascites

Table 2. HRS Diagnostic Criteria New criteria Low glomerular ltration rate (serum creatinine level 1.5 mg/dL or 24-hour creatinine clearance 40 mL/min) Absence of shock, uid losses, and current treatment with nephrotoxic drugs No sustained improvement in renal function after at least 2 days of diuretic withdrawal and expansion of plasma volume with 1 g/kg or maximum 100 g albumin Proteinuria level 400 mg/d and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease

40

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Figure 10. Probability of remaining free from uncontrolled variceal bleeding or variceal rebleeding (left). Probability of survival with endoscopic band ligation (EBL) and TIPS. Reprinted with permission from Garcia-Pagn et al.44

In Fig. 9 are shown the dose responses of a selective V2-receptor antagonist to improve urinary dilution (left) and increase serum sodium concentration (right) in hyponatremic cirrhotic patients.42 As noted earlier, the combined V1/V2-receptor antagonist conivaptan is not approved for hyponatremia in cirrhosis because of the theoretical effect of increasing portal hypertension. The criteria for the rate of increasing serum sodium concentration with a V2 antagonist in cirrhosis and the side effects are similar to those noted earlier for heart failure. Once HRS develops the responsiveness to diuretics is virtually absent. In Table 2 are shown the criteria for diagnosing HRS.43 Type I and type II HRS have substantially different prognoses and different criteria are shown in Table 3. In the past there was virtually no treatment for HRS. Now, however, administration of vasoconstrictors and albumin for 7 to 10 days in patients with type I HRS has shown a temporary reversal of the syndrome in approximately 50% of patients. The primary vasoconstrictors used are terlipressin (V1-receptor agonist) in intravenous boluses 0.4 to 2.0 mg/4 to 6 hours or oral midodrine (2.5-37.5 mg/d, an -adrenergic agonist). This approach has not been investigated in type II HRS but theoretically might be even more effective. The reversal of the HRS after such therapy may last for 30 to 60 days. This would provide time for improvement of any reversible liver injury or obtaining a liver transplant. When these patients respond to the vasoactive and albumin intervention, they again become diuretic responsive. The other treatment for cirrhotic patients with diuretic resistance or HRS is a transjugular intrahepatic portalsystemic shunt (TIPS). In the past, the complications of TIPS in patients with advanced liver disease (Child-Pugh score B or C) was associated with increased hepatic encephalopathy and no change in survival, even though variceal bleeding was controlled. However, a recent randomized trial with early TIPS in cirrhotic patients with Child-Pugh scores of B and C showed better control of initial and rebleeding of varices and improved survival as compared with standard vasoconstrictors and esophageal

variceal banding (Fig. 10).44 There was no difference in the incidence of hepatic encephalopathy.

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