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Cirrhosis With Refractory Ascites: Serial Large Volume Paracentesis, TIPS, or Transplantation?
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:931–935
EDUCATION PRACTICE Cirrhosis With Refractory Ascites: Serial Large Volume Paracentesis, TIPS, or Transplantation? VANDANA KHUNGAR* and SAMMY SAAB*,‡ Departments of *Medicine, and ‡Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
This article has an accompanying continuing medical education activity on page e122. Learning Objectives—At the end of this activity the successful learner will know the diagnostic criteria for refractory ascites, the concept of transient refractoriness, and the clinical algorithm for management of refractory ascites.
See related article, Bhogal HK and Sanyal AJ, on page 936 in this issue of CGH.
Clinical Scenario
A
59-year-old gentleman with cirrhosis from hepatitis C and alcohol was evaluated for suspected refractory ascites. He complained of dyspnea, abdominal distension, and loss of muscle mass. He was treated with furosemide 80 mg and spironolactone 200 mg once daily. We replaced spironolactone with amiloride because of tender gynecomastia. Despite the use of diuretics, he complained of worsening ascites and required weekly or twice weekly paracentesis. He claimed strict adherence to a 2 g sodium diet. The patient had an episode of encephalopathy in the past in the context of an esophageal variceal bleed. He is cachectic on physical examination, with temporal and peripheral muscle wasting. His vitals are: blood pressure 125/ 87, pulse 87 and regular, height 73 inches, and weight 185 pounds. Examinations of his thyroid, heart, and lungs are normal. His abdomen is distended with moderate ascites. Superficial collateral vessels are present on his abdomen. The liver and spleen edge are not palpable because of the large amount of ascites. The skin examination is also remarkable for diffuse spider angiomas across the chest and palmar erythema. His laboratory blood work is remarkable for a serum creatinine of 1.1 g/dL, total bilirubin 2.3 g/dL, platelet count 59,000/mL, albumin 2.4 g/dL, serum sodium 131 mEq/L, 24-hour urine sodium 70 mmol/L. He had been using spontaneous bacterial peritonitis (SBP) prophylaxis at home for low protein ascites (ascites protein 0.7 g/dL). As an outpatient, he underwent 6 L paracentesis approximately every 2 weeks for 4 weeks. While in the hospital, he is restricted to a monitored 2 g sodium diet (80 mmol/L per day) and continued to accumulate ascites, gaining approximately 0.2 kg daily.
The Problem Ascites refers to the accumulation of free fluid in the peritoneum. The most common reason for ascites in the developed world is cirrhosis. Ascites generally responds to both salt restriction and the use of diuretics. It is associated with a poor
quality of life, risk of infections, renal failure, umbilical hernia, malnutrition, muscle wasting, and increased mortality. In patients with ascites, 1- and 5-year survival without liver transplantation is 85% and 56%, respectively. Ascites is occasionally refractory despite salt restriction and the use of diuretics. Defining refractory ascites accurately is critical because ascites is often deemed refractory before truly fitting criteria. Ascites may be suboptimally treated or more aggressive interventions prematurely implemented. The importance of taking a history regarding concomitant medication use and compliance cannot be overstated. The clinical impact of refractory ascites is that it is associated with increased mortality. For instance, 2-year survival in patients with diuretic-resistant ascites is approximately 25%.
The International Ascites Club Definition Refractory ascites is defined as either: (1) diuretic-resistant ascites—ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to dietary sodium restriction and intensive diuretic treatment; or (2) diuretic intractable ascites—ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of the development of diuretic-induced complications that preclude the use of an effective diuretic dosage. The diagnostic criteria for refractory ascites is shown in Table 1.
Management Strategies and Supporting Evidence Ascites becomes refractory in between 5% and 10% of patients with ascites. Transient or apparent refractoriness to diuretic therapy must be ruled out. Transient refractoriness of ascites can occur with renal impairment from other iatrogenic causes or concurrent, reversible complications. Common reaAbbreviations used in this paper: AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of Liver Diseases; HRS, hepatorenal syndrome; LVP, large volume paracentesis; MELD, model for end-stage liver disease; TIPS, transjugular intrahepatic portosystemic shunt. © 2011 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2011.04.028
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Table 1. Revised Diagnostic Criteria of Refractory Ascites (International Ascites Club) 1. Treatment duration: patients must be on intensive diuretic therapy (spironolactone 400 mg by mouth daily and furosemide 160 mg by mouth daily) for at least 1 week and on a sodium restricted diet of less than 90 mmol/L per day or 5.2 g of salt (NaCl) per day. 2. Lack of response: mean weight loss of ⬍0.8 kg over 4 days and urinary sodium output less than the sodium intake. 3. Early ascites recurrence: reappearance of grade 2 or 3 ascites within 4 weeks of initial mobilization. 4. Diuretic-induced complications a. Diuretic-induced hepatic encephalopathy: development of encephalopathy in the absence of any other precipitating factor. b. Diuretic-induced renal impairment: increase of serum creatinine by ⬎100% to a value ⬎2 mg/dL in patients with ascites responding to diuretics. c. Diuretic-induced hyponatremia: decrease of serum sodium by ⬎10 mmol/L to a serum sodium of ⬍125 mmol/L. d. Diuretic-induced hypo- or hyperkalemia: change in serum potassium to ⬍3 mmol/L or ⬎6 mmol/L despite appropriate measures.
sons for transient refractoriness are dietary indiscretion or diuretic prescription lapses. Other causes of transient refractoriness include nonsteroidal anti-inflammatory drug (NSAID) use, administration of angiotensin I-converting-enzyme inhibitors or angiotensin receptor antagonists, or, the administration of nephrotoxic medications. If needed, low sodium dietary compliance can be confirmed by measuring the 24-hour urinary sodium excretion. A patient on a 2 g sodium diet ingests 88 mmol/L of sodium daily, excretes 10 mmol/L in nonurinary loss and should excrete 78 mmol/L in the urine in 24 hours. Patients who gain weight despite excreting more than 78 mmol/L sodium per day are not compliant with the diet. If a patient with a serum sodium concentration of 140 mmol/L consumes 150 mmol/L sodium daily, he would have a positive sodium balance of 72 mmol/L per day or approximately 0.44 kg. A formula to calculate the expected weight gain on a 2 g Na diet is as follows: (patient’s sodium intake in mmol/L ⫺ 10 mmol/L nonurinary loss ⫺ 78 mmol/L urinary loss)/140 mmol/L ⫽ kg weight gain.
Paracentesis Paracentesis with albumin is the treatment of choice for refractory ascites, according to guidelines from the European Association for the Study of Liver Diseases (EASL) and the American Association for the Study of Liver Diseases (AASLD). The procedure should preferably be performed in a hospital setting but can be performed safely in the treating provider’s office. The advantages of paracentesis are that it can be both diagnostic and therapeutic. Paracentesis can provide immediate relief from dyspnea and abdominal distension. As a diagnostic tool, the paracentesis allows for measurement of cell count to assess for peritonitis. When compared with standard diuretic therapy, large volume paracentesis (LVP) with intravenous (IV) albumin infusion is more effective and is associated with fewer complications. Even patients with no urine sodium excretion can have control of their ascites with biweekly paracentesis. If compliant with a low sodium diet, a patient consumes 88 mmol/L of sodium daily, excretes 10 mmol/L per day in nonurinary losses and excretes no urinary sodium, retaining 78 mmol/L per day. A 6 L paracentesis removes 780 mmol/L or approximately 10 days of retained sodium and a 10 L paracentesis removes 17 days of retained sodium (1300 mmol/L) in patients with no urinary sodium excretion. Most studies on paracentesis excluded patients with spontaneous bacterial peritonitis, elevated serum creatinine (⬎3 mg/ dL), severe hepatic encephalopathy, severe thrombocytopenia,
hypotension, or severe jaundice, but there is no clear evidence that these conditions should be considered major contraindications to paracentesis. Although patients with cirrhosis have coagulopathy and thrombocytopenia, significant peritoneal bleeding during paracentesis is approximately 0.5% to 1%. Thus, fresh frozen plasma or platelet transfusions are not recommended as standard procedure. We generally prefer performing a paracentesis at the patient’s left lower quadrant in the office. Ultrasound-guided paracentesis is helpful in patients with ascites found in compartments. Large volume paracentesis should be avoided in patients with disseminated intravascular coagulation.
Transjugular Intrahepatic Portosystemic Shunt (TIPS) A TIPS functions as a side-to-side portacaval shunt, and generally lowers intrahepatic portal pressure. As a result of portal pressure normalization, manifestations of portal hypertension such as ascites and varices significantly improve. Moreover, nutritional status and muscle wasting generally improve. In contrast, muscle wasting continues with LVP, likely because protein is removed in the ascitic fluid with LVP. Large volume paracenteses can be inconvenient and time-consuming for both patients and physicians. Post-TIPS patients must still remain on a low sodium diet as the decrease in sinusoidal portal hypertension post-TIPS results in a very slow increase in urinary sodium excretion of approximately 100 mEq per day at 12 months postprocedure. The results of meta-analyses comparing TIPS with LVP indicate that TIPS is associated with better control of ascites, improved renal function, better nutritional status, and a trend toward increased survival. However, the studies are limited by the heterogeneity of the populations, varied definitions of refractory ascites, and the use of bare metal stents. TIPS stenosis can occur in up to 70% of patients with a bare stent in the first year. Thus, bare stents should not be used. Newer polytetrafluoroethylene (PTFE)-covered stents reduce this complication. New or worsening encephalopathy occurs in 20% to 30% of patients after TIPS. Heart failure, renal failure, and liver failure have been reported after TIPS. TIPS should be avoided in patients with recurrent hepatic encephalopathy. Heart failure and active infections are absolute contraindications to TIPS. TIPS in patients with intrahepatic malignancy can cause dissemination of the tumor. Patients must have a patent portal vein and no structural abnormalities such as multiple hepatic cysts.
November 2011
Peritoneovenous Shunt Peritoneovenous shunt (LeVeen or Denver) was used in the 1970s and was shown to decrease duration and number of hospitalizations as well as dose of diuretics. Because of poor long-term patency, complications and lack of survival advantage compared with medical therapy, peritoneovenous shunts are almost never performed for ascites today. Shunting should now be reserved for patients who are not candidates for transplant or TIPS and are not candidates for multiple LVPs because of surgical scars or distance from a medical facility with the ability to do LVPs. If surgical scars are associated with loculated ascites, peritoneovenous shunt will not be effective.
Orthotopic Liver Transplantation Liver transplantation is the ultimate treatment of advanced liver disease and its complications. However, the current organ allocation system, using the model for end-stage liver disease (MELD) score, does not consider manifestations of portal hypertension such as ascites. The addition of sodium to the MELD score, perhaps a surrogate marker of ascites severity and mortality, improves the accuracy in predicting survival particularly in patients with low MELD score values. Some United Network of Organ Sharing (UNOS) liver transplant regions recognize that the MELD score may not accurately predict survival in patients with refractory ascites. As a result, some United Network for Organ Sharing regions allow MELD exceptions in patients who meet specific criteria.
Areas of Uncertainty There are several areas of uncertainty in the treatment of refractory ascites. For instance, EASL guidelines suggest the use of colloid replacement after paracentesis but the implementation of these guidelines in practice is not universal. The argument for using colloid replacement is to prevent paracentesis-induced circulatory dysfunction (PICD), effective hypovolemia, and renal impairment. Albumin has been shown to help prevent paracentesis-induced circulatory dysfunction when a volume of greater than 5 L of ascites is removed during paracentesis. However, the use of albumin can be cumbersome and costly; for this reason, some clinicians do not routinely administer albumin. Some of the recently published guidelines (including EASL 2010 – level IA, and AASLD 2009 – IIA, level C), recommend the use of albumin for patients treated with LVP of more than 5 L. One study of 105 patients with tense ascites randomized to albumin (10 g/L fluid removed) versus no albumin after large volume paracentesis showed that the group who did not receive albumin developed more changes in electrolytes, plasma rennin, and serum creatinine. Study protocols have included between 5 and 10 g of albumin per liter of fluid removed. No study to date has compared doses of albumin. In Europe, only a 20% albumin solution is available whereas in the US, 5% and 25% isotonic solutions are available. Infusion of the 5% solution increases sodium load 5 times that of the 25% solution. Some of the controversy surrounding postparacentesis plasma expanders relates to study design—in current studies, populations are not diuretic-resistant, survival was not a studyspecific endpoint, and doses are not compared. Nonalbumin plasma expanders such as dextran 70, hydroxyethylstarch, and saline have also been advocated, but have not demonstrated survival advantage. Hydroxethylstarch can fill Kupffer cells and
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cause portal hypertension even in those without portal hypertension. The amount of ascites removed at paracentesis and the frequency of paracentesis are not readily agreed upon. Even patients with no urinary sodium excretion will have their ascites controlled with paracentesis every 2 weeks. This approach has been proven to be safe and effective in controlled trials. The frequency of paracentesis needed allows the clinician to assess compliance with a low sodium diet. The sodium concentration of ascitic fluid is approximately equivalent to that of plasma in cirrhotic patients with ascites (approximately 130 mmol/L). In a 6 L paracentesis, 780 mmol/L of sodium are removed (130 mmol/L ⫻ 6 L ⫽ 780 mmol/L) and 1300 mmol/L are removed in a 10 L paracentesis. If a patient has no urinary excretion of sodium and consumes 88 mmol/L of sodium daily, and excretes 10 mmol/L daily in nonurinary losses, they retain 78 mmol/L of sodium. For these patients, a 6 L paracentesis removes 10 days of sodium and 10 L paracentesis removes 17 days of sodium. Patients with a small amount of urinary sodium excretion require paracentesis less frequently. Hyponatremia frequently accompanies refractory ascites, believed to be a result of increased vasopressin release. Currently, the treatment of hyponatremia is indicated when serum sodium is less than 125 mEq/L and revolves around fluid restriction. There has been increasing interest in using aquaretics to treat hyponatremia. Aquaretics antagonize the V2 receptors, increasing free water excretion and thus serum sodium concentrations. The results of recent randomized controlled trials (RCTs) demonstrated that oral tolvaptan was superior to placebo in correcting hyponatremia secondary to cirrhosis. A major concern is rapid correction of serum sodium, leading to irreversible central pontine myelinolysis. Because of the need for close electrolyte monitoring, aquaretic treatment must be initiated in the hospital setting. When type 2 hepatorenal syndrome occurs with refractory ascites, it can be controversial whether to proceed to TIPS, large volume paracentesis, or combined liver-kidney transplant. Large volume paracentesis can worsen hepatorenal syndrome (HRS) by increasing plasma renin approximately 1 week after paracentesis. TIPS has been proposed as an alternative to paracentesis as it reduces filtration pressure and increases urinary sodium excretion, urinary volume, and improves plasma creatinine concentration. Plasma renin activity, aldosterone, and noradrenalin concentrations also improve gradually after TIPS, suggesting a positive effect on systemic underfilling. Patients must be considered carefully for TIPS as outlined above and if they are appropriate candidates, this is a viable alternative to LVP for HRS. A recent study addreses the issue of which patients with HRS should receive a dual transplant. A retrospective series of 148 patients by Ruiz et al showed that patients who required hemodialysis for longer than 8 weeks prior to transplant had a better outcome after combined transplantation than after liver transplantation. This study suggested kidney after liver transplantation as an option in patients with HRS and persistent posttransplant renal dysfunction of at least 60 days’ duration. Another study by Davis et al suggests that orthotopic liver transplant candidates on dialysis for ⬎6 weeks pretransplant receive dual liver-kidney transplants. There is still no consensus though on which patients should receive a dual transplant. It is our institution’s practice to consider dual liver/kidney transplantation in patients on hemodialysis for more than 4 weeks.
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Figure 1. Suggested approach to the cirrhotic patient with ascites not responsive to diuretics. GI, gastrointestinal; NSAID, nonsteroidal antiinflammatory drug; OLT, orthotopic liver transplant; SBP, spontaneous bacterial peritonitis. †Lack of response defined as mean weight loss ⬍0.8 kg over 4 days and urinary sodium output less than sodium intake on intensive diuretic therapy (spironolactone 400 mg by mouth daily and furosemide 160 mg by mouth daily) for at least 1 week and on a sodium restricted diet of ⬍90 mmol/L per day or 5.2 g of salt per day. ‡Refractory ascites defined by the International Ascites Club is either: (1) diuretic resistant ascites—ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to dietary sodium restriction and intensive diuretic treatment; or (2) diuretic-intractable ascites—ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of the development of diuretic-induced complications that preclude the use of an effective diuretic dosage.
Other treatment strategies that are emerging for refractory ascites include the sole use or combination of albumin infusion, midodrine, and subcutaneous octreotide. However, further trials are needed before these experimental therapies can be recommended in routine clinical practice.
Society Guidelines Two hepatology associations have published clinical guidelines for the treatment of refractory ascites. The AASLD
guidelines on the management of ascites were published in 2009. Class I recommendations include: serial LVPs are a treatment option for refractory ascites, postparacentesis albumin infusion is not necessary for a single paracentesis of less than 4 to 5 L, TIPS may be considered in appropriately selected patients who meet criteria similar to those of published randomized trials. The EASL guidelines were published in 2010. Repeated LVP with albumin is the first line of therapy for refractory ascites and diuretics should be discon-
Table 2. Available Diuretics and Aquaretics for Treatment of Ascites and Hyponatremia Diuretic/aquaretic Aldosterone antagonists Spironolactone Eplerenone Loop diuretic Furosemide Epithelial sodium channel blocker Amiloride Aquaretic (vasopressin antagonist) Tolvaptan
Usual adult dose (mg)
Time to peak effect (h)
Duration of action
100–400 100–400
48 1.5
2–3 days 2–3 days
44–176 200–400
40–160
1–2
6–8 hours
14–56
5–20
6–10
24 hours
50–200
2–4
12 hours
9000–36,000
15–60
Average wholesale price (30 d; US$)
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tinued in those with refractory ascites who do not excrete ⬎30 mmol/L per day of sodium with diuretic use. Assessment of response of ascites to diuretic therapy and salt restriction should be performed only in stable patients without associated complications such as bleeding or infection. Patients with refractory ascites should be considered for orthotopic liver transplant. TIPS is effective for refractory ascites but is associated with a high risk of hepatic encephalopathy and has not been shown convincingly to improve survival. TIPS should be considered in patients who require very frequent LVP or in whom paracentesis is ineffective because of loculated ascites. TIPS is not recommended in patients with severe liver failure (serum bilirubin ⬎5 mg/dL, international normalized ratio ⬎2, or Child–Pugh score ⬎11, current hepatic encephalopathy ⱖgrade 2 or chronic hepatic encephalopathy), concomitant active infection, progressive renal failure, or severe cardiopulmonary disease. The AASLD and EASL guidelines favor therapies with robust evidence from randomized controlled trials (RCTs). Combining the evidence from the guidelines, an approach to the patient with refractory ascites is presented in Figure 1. Characteristics of the pharmacologic agents available for ascites and hyponatremia are presented in Table 2. Some of the newer experimental therapies as well as covered stents in TIPS which have not undergone extensive evaluation may prove to be superior options for the treatment of refractory ascites.
Summary The patient was admitted to the hospital for further evaluation and possible TIPS. On admission, the patient’s furosemide and amiloride were continued at previously prescribed doses. Urine sodium was 70 mmol/L on a 90 mmol/L sodium per day diet. A Doppler ultrasound of the abdominal vessels showed patent portal vein, hepatic vein and artery, and inferior vena cava with appropriate direction of flow. With increasing diuretic doses, the patient’s creatinine rose from 1.1 to 2.5 mg/dL. His urine output decreased and he was felt to have developed hepatorenal syndrome. On the morning the patient was scheduled for TIPS for his refractory ascites, he was noted to be grossly encephalopathic. His bilirubin increased to 8 mg/dL and his international normalized ratio to 2.7 mg/dL. He underwent a full infectious workup including diagnostic paracentesis and no source of infection was found. A decision was made to forgo TIPS and the patient was listed for orthotopic liver transplantation, which he received 2 months later.
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Suggested Reading 1. Runyon BA, AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009;49:2087–2107. 2. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53:397– 417. 3. Salerno F, Guevara M, Bernardi M, et al. Refractory ascites: pathogenesis, definition and therapy of a severe complication in patients with cirrhosis. Liver Int 2010;30:937–947. 4. Senousy BE, Draganov PV. Evaluation and management of patients with refractory ascites. World J Gastroenterol 2009;15: 67– 80. 5. Wong F, Gines P, Watson H, et al. Effects of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites recurrence after paracentesis in patients with cirrhosis. J Hepatol 2010;53:283–290. 6. Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010;21:705–712. 7. Somsouk M, Kornfield R, Vittinghoff E, et al. Moderate ascites identifies patients with low model for end-stage liver disease scores awaiting liver transplantation who have a high mortality risk. Liver Transplant 2011;17:129 –136. 8. Moore KP, Wong F, Gines P, et al. The management of ascites in cirrhosis: report on the consensus conference of the international ascites club. Hepatology 2003;38:258 –266. 9. Ginès P, Titó L, Arroyo V, et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988;94:1493–1502. 10. Lacy CF. Drug Information Handbook 2010/2011, 19th ed, Hudson, OH: Lexi-Comp, 2010. 11. Davis CL, Feng S, Sung R, et al. Simultaneous liver-kidney transplantation: evaluation to decision making. Am J Transplant 2007; 7:1702–1709. 12. Ruiz R, Barri YM, Jennings LW, et al. Hepatorenal syndrome: a proposal for kidney after liver transplantation (KALT). Liver Transplant 2007;13:838 – 843.
Reprint requests Address requests for reprints to: Sammy Saab, MD, MPH, AGAF, Pfleger Liver Institute, UCLA Medical Center, 200 Medical Plaza, Suite 214, Los Angeles, California 90095. e-mail: [email protected]. edu; fax: (310) 206-4197. Acknowledgments The authors thank Noel Ayoub for his assistance with figure construction. Conflicts of interest The authors disclose no conflicts.
EDUCATION PRACTICE Cirrhosis With Refractory Ascites: Serial Large Volume Paracentesis, TIPS, or Transplantation? VANDANA KHUNGAR* and SAMMY SAAB*,‡ Departments of *Medicine, and ‡Surgery, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
This article has an accompanying continuing medical education activity on page e122. Learning Objectives—At the end of this activity the successful learner will know the diagnostic criteria for refractory ascites, the concept of transient refractoriness, and the clinical algorithm for management of refractory ascites.
See related article, Bhogal HK and Sanyal AJ, on page 936 in this issue of CGH.
Clinical Scenario
A
59-year-old gentleman with cirrhosis from hepatitis C and alcohol was evaluated for suspected refractory ascites. He complained of dyspnea, abdominal distension, and loss of muscle mass. He was treated with furosemide 80 mg and spironolactone 200 mg once daily. We replaced spironolactone with amiloride because of tender gynecomastia. Despite the use of diuretics, he complained of worsening ascites and required weekly or twice weekly paracentesis. He claimed strict adherence to a 2 g sodium diet. The patient had an episode of encephalopathy in the past in the context of an esophageal variceal bleed. He is cachectic on physical examination, with temporal and peripheral muscle wasting. His vitals are: blood pressure 125/ 87, pulse 87 and regular, height 73 inches, and weight 185 pounds. Examinations of his thyroid, heart, and lungs are normal. His abdomen is distended with moderate ascites. Superficial collateral vessels are present on his abdomen. The liver and spleen edge are not palpable because of the large amount of ascites. The skin examination is also remarkable for diffuse spider angiomas across the chest and palmar erythema. His laboratory blood work is remarkable for a serum creatinine of 1.1 g/dL, total bilirubin 2.3 g/dL, platelet count 59,000/mL, albumin 2.4 g/dL, serum sodium 131 mEq/L, 24-hour urine sodium 70 mmol/L. He had been using spontaneous bacterial peritonitis (SBP) prophylaxis at home for low protein ascites (ascites protein 0.7 g/dL). As an outpatient, he underwent 6 L paracentesis approximately every 2 weeks for 4 weeks. While in the hospital, he is restricted to a monitored 2 g sodium diet (80 mmol/L per day) and continued to accumulate ascites, gaining approximately 0.2 kg daily.
The Problem Ascites refers to the accumulation of free fluid in the peritoneum. The most common reason for ascites in the developed world is cirrhosis. Ascites generally responds to both salt restriction and the use of diuretics. It is associated with a poor
quality of life, risk of infections, renal failure, umbilical hernia, malnutrition, muscle wasting, and increased mortality. In patients with ascites, 1- and 5-year survival without liver transplantation is 85% and 56%, respectively. Ascites is occasionally refractory despite salt restriction and the use of diuretics. Defining refractory ascites accurately is critical because ascites is often deemed refractory before truly fitting criteria. Ascites may be suboptimally treated or more aggressive interventions prematurely implemented. The importance of taking a history regarding concomitant medication use and compliance cannot be overstated. The clinical impact of refractory ascites is that it is associated with increased mortality. For instance, 2-year survival in patients with diuretic-resistant ascites is approximately 25%.
The International Ascites Club Definition Refractory ascites is defined as either: (1) diuretic-resistant ascites—ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to dietary sodium restriction and intensive diuretic treatment; or (2) diuretic intractable ascites—ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of the development of diuretic-induced complications that preclude the use of an effective diuretic dosage. The diagnostic criteria for refractory ascites is shown in Table 1.
Management Strategies and Supporting Evidence Ascites becomes refractory in between 5% and 10% of patients with ascites. Transient or apparent refractoriness to diuretic therapy must be ruled out. Transient refractoriness of ascites can occur with renal impairment from other iatrogenic causes or concurrent, reversible complications. Common reaAbbreviations used in this paper: AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of Liver Diseases; HRS, hepatorenal syndrome; LVP, large volume paracentesis; MELD, model for end-stage liver disease; TIPS, transjugular intrahepatic portosystemic shunt. © 2011 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2011.04.028
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Table 1. Revised Diagnostic Criteria of Refractory Ascites (International Ascites Club) 1. Treatment duration: patients must be on intensive diuretic therapy (spironolactone 400 mg by mouth daily and furosemide 160 mg by mouth daily) for at least 1 week and on a sodium restricted diet of less than 90 mmol/L per day or 5.2 g of salt (NaCl) per day. 2. Lack of response: mean weight loss of ⬍0.8 kg over 4 days and urinary sodium output less than the sodium intake. 3. Early ascites recurrence: reappearance of grade 2 or 3 ascites within 4 weeks of initial mobilization. 4. Diuretic-induced complications a. Diuretic-induced hepatic encephalopathy: development of encephalopathy in the absence of any other precipitating factor. b. Diuretic-induced renal impairment: increase of serum creatinine by ⬎100% to a value ⬎2 mg/dL in patients with ascites responding to diuretics. c. Diuretic-induced hyponatremia: decrease of serum sodium by ⬎10 mmol/L to a serum sodium of ⬍125 mmol/L. d. Diuretic-induced hypo- or hyperkalemia: change in serum potassium to ⬍3 mmol/L or ⬎6 mmol/L despite appropriate measures.
sons for transient refractoriness are dietary indiscretion or diuretic prescription lapses. Other causes of transient refractoriness include nonsteroidal anti-inflammatory drug (NSAID) use, administration of angiotensin I-converting-enzyme inhibitors or angiotensin receptor antagonists, or, the administration of nephrotoxic medications. If needed, low sodium dietary compliance can be confirmed by measuring the 24-hour urinary sodium excretion. A patient on a 2 g sodium diet ingests 88 mmol/L of sodium daily, excretes 10 mmol/L in nonurinary loss and should excrete 78 mmol/L in the urine in 24 hours. Patients who gain weight despite excreting more than 78 mmol/L sodium per day are not compliant with the diet. If a patient with a serum sodium concentration of 140 mmol/L consumes 150 mmol/L sodium daily, he would have a positive sodium balance of 72 mmol/L per day or approximately 0.44 kg. A formula to calculate the expected weight gain on a 2 g Na diet is as follows: (patient’s sodium intake in mmol/L ⫺ 10 mmol/L nonurinary loss ⫺ 78 mmol/L urinary loss)/140 mmol/L ⫽ kg weight gain.
Paracentesis Paracentesis with albumin is the treatment of choice for refractory ascites, according to guidelines from the European Association for the Study of Liver Diseases (EASL) and the American Association for the Study of Liver Diseases (AASLD). The procedure should preferably be performed in a hospital setting but can be performed safely in the treating provider’s office. The advantages of paracentesis are that it can be both diagnostic and therapeutic. Paracentesis can provide immediate relief from dyspnea and abdominal distension. As a diagnostic tool, the paracentesis allows for measurement of cell count to assess for peritonitis. When compared with standard diuretic therapy, large volume paracentesis (LVP) with intravenous (IV) albumin infusion is more effective and is associated with fewer complications. Even patients with no urine sodium excretion can have control of their ascites with biweekly paracentesis. If compliant with a low sodium diet, a patient consumes 88 mmol/L of sodium daily, excretes 10 mmol/L per day in nonurinary losses and excretes no urinary sodium, retaining 78 mmol/L per day. A 6 L paracentesis removes 780 mmol/L or approximately 10 days of retained sodium and a 10 L paracentesis removes 17 days of retained sodium (1300 mmol/L) in patients with no urinary sodium excretion. Most studies on paracentesis excluded patients with spontaneous bacterial peritonitis, elevated serum creatinine (⬎3 mg/ dL), severe hepatic encephalopathy, severe thrombocytopenia,
hypotension, or severe jaundice, but there is no clear evidence that these conditions should be considered major contraindications to paracentesis. Although patients with cirrhosis have coagulopathy and thrombocytopenia, significant peritoneal bleeding during paracentesis is approximately 0.5% to 1%. Thus, fresh frozen plasma or platelet transfusions are not recommended as standard procedure. We generally prefer performing a paracentesis at the patient’s left lower quadrant in the office. Ultrasound-guided paracentesis is helpful in patients with ascites found in compartments. Large volume paracentesis should be avoided in patients with disseminated intravascular coagulation.
Transjugular Intrahepatic Portosystemic Shunt (TIPS) A TIPS functions as a side-to-side portacaval shunt, and generally lowers intrahepatic portal pressure. As a result of portal pressure normalization, manifestations of portal hypertension such as ascites and varices significantly improve. Moreover, nutritional status and muscle wasting generally improve. In contrast, muscle wasting continues with LVP, likely because protein is removed in the ascitic fluid with LVP. Large volume paracenteses can be inconvenient and time-consuming for both patients and physicians. Post-TIPS patients must still remain on a low sodium diet as the decrease in sinusoidal portal hypertension post-TIPS results in a very slow increase in urinary sodium excretion of approximately 100 mEq per day at 12 months postprocedure. The results of meta-analyses comparing TIPS with LVP indicate that TIPS is associated with better control of ascites, improved renal function, better nutritional status, and a trend toward increased survival. However, the studies are limited by the heterogeneity of the populations, varied definitions of refractory ascites, and the use of bare metal stents. TIPS stenosis can occur in up to 70% of patients with a bare stent in the first year. Thus, bare stents should not be used. Newer polytetrafluoroethylene (PTFE)-covered stents reduce this complication. New or worsening encephalopathy occurs in 20% to 30% of patients after TIPS. Heart failure, renal failure, and liver failure have been reported after TIPS. TIPS should be avoided in patients with recurrent hepatic encephalopathy. Heart failure and active infections are absolute contraindications to TIPS. TIPS in patients with intrahepatic malignancy can cause dissemination of the tumor. Patients must have a patent portal vein and no structural abnormalities such as multiple hepatic cysts.
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Peritoneovenous Shunt Peritoneovenous shunt (LeVeen or Denver) was used in the 1970s and was shown to decrease duration and number of hospitalizations as well as dose of diuretics. Because of poor long-term patency, complications and lack of survival advantage compared with medical therapy, peritoneovenous shunts are almost never performed for ascites today. Shunting should now be reserved for patients who are not candidates for transplant or TIPS and are not candidates for multiple LVPs because of surgical scars or distance from a medical facility with the ability to do LVPs. If surgical scars are associated with loculated ascites, peritoneovenous shunt will not be effective.
Orthotopic Liver Transplantation Liver transplantation is the ultimate treatment of advanced liver disease and its complications. However, the current organ allocation system, using the model for end-stage liver disease (MELD) score, does not consider manifestations of portal hypertension such as ascites. The addition of sodium to the MELD score, perhaps a surrogate marker of ascites severity and mortality, improves the accuracy in predicting survival particularly in patients with low MELD score values. Some United Network of Organ Sharing (UNOS) liver transplant regions recognize that the MELD score may not accurately predict survival in patients with refractory ascites. As a result, some United Network for Organ Sharing regions allow MELD exceptions in patients who meet specific criteria.
Areas of Uncertainty There are several areas of uncertainty in the treatment of refractory ascites. For instance, EASL guidelines suggest the use of colloid replacement after paracentesis but the implementation of these guidelines in practice is not universal. The argument for using colloid replacement is to prevent paracentesis-induced circulatory dysfunction (PICD), effective hypovolemia, and renal impairment. Albumin has been shown to help prevent paracentesis-induced circulatory dysfunction when a volume of greater than 5 L of ascites is removed during paracentesis. However, the use of albumin can be cumbersome and costly; for this reason, some clinicians do not routinely administer albumin. Some of the recently published guidelines (including EASL 2010 – level IA, and AASLD 2009 – IIA, level C), recommend the use of albumin for patients treated with LVP of more than 5 L. One study of 105 patients with tense ascites randomized to albumin (10 g/L fluid removed) versus no albumin after large volume paracentesis showed that the group who did not receive albumin developed more changes in electrolytes, plasma rennin, and serum creatinine. Study protocols have included between 5 and 10 g of albumin per liter of fluid removed. No study to date has compared doses of albumin. In Europe, only a 20% albumin solution is available whereas in the US, 5% and 25% isotonic solutions are available. Infusion of the 5% solution increases sodium load 5 times that of the 25% solution. Some of the controversy surrounding postparacentesis plasma expanders relates to study design—in current studies, populations are not diuretic-resistant, survival was not a studyspecific endpoint, and doses are not compared. Nonalbumin plasma expanders such as dextran 70, hydroxyethylstarch, and saline have also been advocated, but have not demonstrated survival advantage. Hydroxethylstarch can fill Kupffer cells and
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cause portal hypertension even in those without portal hypertension. The amount of ascites removed at paracentesis and the frequency of paracentesis are not readily agreed upon. Even patients with no urinary sodium excretion will have their ascites controlled with paracentesis every 2 weeks. This approach has been proven to be safe and effective in controlled trials. The frequency of paracentesis needed allows the clinician to assess compliance with a low sodium diet. The sodium concentration of ascitic fluid is approximately equivalent to that of plasma in cirrhotic patients with ascites (approximately 130 mmol/L). In a 6 L paracentesis, 780 mmol/L of sodium are removed (130 mmol/L ⫻ 6 L ⫽ 780 mmol/L) and 1300 mmol/L are removed in a 10 L paracentesis. If a patient has no urinary excretion of sodium and consumes 88 mmol/L of sodium daily, and excretes 10 mmol/L daily in nonurinary losses, they retain 78 mmol/L of sodium. For these patients, a 6 L paracentesis removes 10 days of sodium and 10 L paracentesis removes 17 days of sodium. Patients with a small amount of urinary sodium excretion require paracentesis less frequently. Hyponatremia frequently accompanies refractory ascites, believed to be a result of increased vasopressin release. Currently, the treatment of hyponatremia is indicated when serum sodium is less than 125 mEq/L and revolves around fluid restriction. There has been increasing interest in using aquaretics to treat hyponatremia. Aquaretics antagonize the V2 receptors, increasing free water excretion and thus serum sodium concentrations. The results of recent randomized controlled trials (RCTs) demonstrated that oral tolvaptan was superior to placebo in correcting hyponatremia secondary to cirrhosis. A major concern is rapid correction of serum sodium, leading to irreversible central pontine myelinolysis. Because of the need for close electrolyte monitoring, aquaretic treatment must be initiated in the hospital setting. When type 2 hepatorenal syndrome occurs with refractory ascites, it can be controversial whether to proceed to TIPS, large volume paracentesis, or combined liver-kidney transplant. Large volume paracentesis can worsen hepatorenal syndrome (HRS) by increasing plasma renin approximately 1 week after paracentesis. TIPS has been proposed as an alternative to paracentesis as it reduces filtration pressure and increases urinary sodium excretion, urinary volume, and improves plasma creatinine concentration. Plasma renin activity, aldosterone, and noradrenalin concentrations also improve gradually after TIPS, suggesting a positive effect on systemic underfilling. Patients must be considered carefully for TIPS as outlined above and if they are appropriate candidates, this is a viable alternative to LVP for HRS. A recent study addreses the issue of which patients with HRS should receive a dual transplant. A retrospective series of 148 patients by Ruiz et al showed that patients who required hemodialysis for longer than 8 weeks prior to transplant had a better outcome after combined transplantation than after liver transplantation. This study suggested kidney after liver transplantation as an option in patients with HRS and persistent posttransplant renal dysfunction of at least 60 days’ duration. Another study by Davis et al suggests that orthotopic liver transplant candidates on dialysis for ⬎6 weeks pretransplant receive dual liver-kidney transplants. There is still no consensus though on which patients should receive a dual transplant. It is our institution’s practice to consider dual liver/kidney transplantation in patients on hemodialysis for more than 4 weeks.
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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 11
Figure 1. Suggested approach to the cirrhotic patient with ascites not responsive to diuretics. GI, gastrointestinal; NSAID, nonsteroidal antiinflammatory drug; OLT, orthotopic liver transplant; SBP, spontaneous bacterial peritonitis. †Lack of response defined as mean weight loss ⬍0.8 kg over 4 days and urinary sodium output less than sodium intake on intensive diuretic therapy (spironolactone 400 mg by mouth daily and furosemide 160 mg by mouth daily) for at least 1 week and on a sodium restricted diet of ⬍90 mmol/L per day or 5.2 g of salt per day. ‡Refractory ascites defined by the International Ascites Club is either: (1) diuretic resistant ascites—ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to dietary sodium restriction and intensive diuretic treatment; or (2) diuretic-intractable ascites—ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of the development of diuretic-induced complications that preclude the use of an effective diuretic dosage.
Other treatment strategies that are emerging for refractory ascites include the sole use or combination of albumin infusion, midodrine, and subcutaneous octreotide. However, further trials are needed before these experimental therapies can be recommended in routine clinical practice.
Society Guidelines Two hepatology associations have published clinical guidelines for the treatment of refractory ascites. The AASLD
guidelines on the management of ascites were published in 2009. Class I recommendations include: serial LVPs are a treatment option for refractory ascites, postparacentesis albumin infusion is not necessary for a single paracentesis of less than 4 to 5 L, TIPS may be considered in appropriately selected patients who meet criteria similar to those of published randomized trials. The EASL guidelines were published in 2010. Repeated LVP with albumin is the first line of therapy for refractory ascites and diuretics should be discon-
Table 2. Available Diuretics and Aquaretics for Treatment of Ascites and Hyponatremia Diuretic/aquaretic Aldosterone antagonists Spironolactone Eplerenone Loop diuretic Furosemide Epithelial sodium channel blocker Amiloride Aquaretic (vasopressin antagonist) Tolvaptan
Usual adult dose (mg)
Time to peak effect (h)
Duration of action
100–400 100–400
48 1.5
2–3 days 2–3 days
44–176 200–400
40–160
1–2
6–8 hours
14–56
5–20
6–10
24 hours
50–200
2–4
12 hours
9000–36,000
15–60
Average wholesale price (30 d; US$)
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tinued in those with refractory ascites who do not excrete ⬎30 mmol/L per day of sodium with diuretic use. Assessment of response of ascites to diuretic therapy and salt restriction should be performed only in stable patients without associated complications such as bleeding or infection. Patients with refractory ascites should be considered for orthotopic liver transplant. TIPS is effective for refractory ascites but is associated with a high risk of hepatic encephalopathy and has not been shown convincingly to improve survival. TIPS should be considered in patients who require very frequent LVP or in whom paracentesis is ineffective because of loculated ascites. TIPS is not recommended in patients with severe liver failure (serum bilirubin ⬎5 mg/dL, international normalized ratio ⬎2, or Child–Pugh score ⬎11, current hepatic encephalopathy ⱖgrade 2 or chronic hepatic encephalopathy), concomitant active infection, progressive renal failure, or severe cardiopulmonary disease. The AASLD and EASL guidelines favor therapies with robust evidence from randomized controlled trials (RCTs). Combining the evidence from the guidelines, an approach to the patient with refractory ascites is presented in Figure 1. Characteristics of the pharmacologic agents available for ascites and hyponatremia are presented in Table 2. Some of the newer experimental therapies as well as covered stents in TIPS which have not undergone extensive evaluation may prove to be superior options for the treatment of refractory ascites.
Summary The patient was admitted to the hospital for further evaluation and possible TIPS. On admission, the patient’s furosemide and amiloride were continued at previously prescribed doses. Urine sodium was 70 mmol/L on a 90 mmol/L sodium per day diet. A Doppler ultrasound of the abdominal vessels showed patent portal vein, hepatic vein and artery, and inferior vena cava with appropriate direction of flow. With increasing diuretic doses, the patient’s creatinine rose from 1.1 to 2.5 mg/dL. His urine output decreased and he was felt to have developed hepatorenal syndrome. On the morning the patient was scheduled for TIPS for his refractory ascites, he was noted to be grossly encephalopathic. His bilirubin increased to 8 mg/dL and his international normalized ratio to 2.7 mg/dL. He underwent a full infectious workup including diagnostic paracentesis and no source of infection was found. A decision was made to forgo TIPS and the patient was listed for orthotopic liver transplantation, which he received 2 months later.
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Suggested Reading 1. Runyon BA, AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009;49:2087–2107. 2. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53:397– 417. 3. Salerno F, Guevara M, Bernardi M, et al. Refractory ascites: pathogenesis, definition and therapy of a severe complication in patients with cirrhosis. Liver Int 2010;30:937–947. 4. Senousy BE, Draganov PV. Evaluation and management of patients with refractory ascites. World J Gastroenterol 2009;15: 67– 80. 5. Wong F, Gines P, Watson H, et al. Effects of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites recurrence after paracentesis in patients with cirrhosis. J Hepatol 2010;53:283–290. 6. Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010;21:705–712. 7. Somsouk M, Kornfield R, Vittinghoff E, et al. Moderate ascites identifies patients with low model for end-stage liver disease scores awaiting liver transplantation who have a high mortality risk. Liver Transplant 2011;17:129 –136. 8. Moore KP, Wong F, Gines P, et al. The management of ascites in cirrhosis: report on the consensus conference of the international ascites club. Hepatology 2003;38:258 –266. 9. Ginès P, Titó L, Arroyo V, et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988;94:1493–1502. 10. Lacy CF. Drug Information Handbook 2010/2011, 19th ed, Hudson, OH: Lexi-Comp, 2010. 11. Davis CL, Feng S, Sung R, et al. Simultaneous liver-kidney transplantation: evaluation to decision making. Am J Transplant 2007; 7:1702–1709. 12. Ruiz R, Barri YM, Jennings LW, et al. Hepatorenal syndrome: a proposal for kidney after liver transplantation (KALT). Liver Transplant 2007;13:838 – 843.
Reprint requests Address requests for reprints to: Sammy Saab, MD, MPH, AGAF, Pfleger Liver Institute, UCLA Medical Center, 200 Medical Plaza, Suite 214, Los Angeles, California 90095. e-mail: [email protected]. edu; fax: (310) 206-4197. Acknowledgments The authors thank Noel Ayoub for his assistance with figure construction. Conflicts of interest The authors disclose no conflicts.