Management of ascites in cirrhosis

Authors


Dr Florence Wong, 9th floor, North Wing, Room 983, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON M5G2C4, Canada. Email: florence.wong@utoronto.ca

Abstract

Ascites is a common complication of liver cirrhosis associated with a poor prognosis. The treatment of ascites requires dietary sodium restriction and the judicious use of distal and loop diuretics, sequential at an earlier stage of ascites, and a combination at a later stage of ascites. The diagnosis of refractory ascites requires the demonstration of diuretic non-responsiveness, despite dietary sodium restriction, or the presence of diuretic-related complications. Patients with refractory ascites require second-line treatments of repeat large-volume paracentesis (LVP) or the insertion of a transjugular intrahepatic portosystemic shunt (TIPS), and assessment for liver transplantation. Careful patient selection is paramount for TIPS to be successful as a treatment for ascites. Patients not suitable for TIPS insertion should receive LVP. The use of albumin as a volume expander is recommended for LVP of >5–6 L to prevent the development of circulatory dysfunction, although the clinical significance of post-paracentesis circulatory dysfunction is still debated. Significant mortality is still being observed in cirrhotic patients with ascites and relatively preserved liver and renal function, as indicated by a lower Model for End-Stage Liver Disease (MELD) score. It is proposed that patients with lower MELD scores and ascites should receive additional points in calculating their priority for liver transplantation. Potential new treatment options for ascites include the use of various vasoconstrictors, vasopressin V2 receptor antagonists, or the insertion of a peritoneo-vesical shunt, all of which could possibly improve the management of ascites.

Introduction

The risk for developing ascites is approximately 60% at 10 years after cirrhosis diagnosis if the underlying cause of the cirrhosis is left untreated.1 The appearance of ascites heralds the onset of decompensation, and the survival of these patients changes from 80% at 5 years1 to 50% at 5 years2 without liver transplantation. This is because the hemodynamic changes and circulatory dysfunction that accompany the progression of cirrhosis predispose these patients to other complications (Fig. 1) associated with worsening prognosis (Table 1).3 In a study assessing the natural history of patients with cirrhosis, hospitalized for the management of ascites, during a mean follow-up period of 41 ± 3 months, 28% of 263 patients developed dilutional hyponatremia, 11% developed refractory ascites, and 7.6% developed hepatorenal syndrome (HRS). The occurrence of any of these complications further reduced survival2 (Fig. 2).

Figure 1.

Stages of ascites in cirrhosis. HRS, hepatorenal syndrome. inline image = spontaneous bacterial peritonitis.

Table 1.  Prognosis factors in cirrhotic patients with ascites
ParameterMedian survival (months)
  1. Na, sodium. Adapted from Cardenas and Arroyo,3 with permission.

Mean arterial pressure (mmHg) 
 > 8046
 < 8011
Serum creatinine (mg/dL) 
 < 1.225
 1.2–1.511
 ≥ 1.54
Hyponatremia (serum [Na] < 130 mmEq/L) 
 No27
 Yes7
Urinary Na excretion (mmEq/day) 
 ≥ 1046
 < 1017
Plasma renin activity 
 Normal57
 Increased6
Plasma norepinephrine (epinephrine) 
 Normal23
 Increased13
Figure 2.

Survival of hospitalized patients with ascites with or without complications. (Adapted from Planas et al.,2 with permission.) inline image, No complications; inline image, Spontaneous bacterial peritonitis; inline image, Refractory ascites; inline image, Dilutional hyponatremia; inline image, Hepatorenal syndrome.

The effective treatment of ascites in cirrhosis involves correcting one or more of the pathophysiological processes that lead to ascites formation (Fig. 3). In short, the presence of cirrhosis and portal hypertension leads to vasodilatation in the systemic and splanchnic circulations, but vasoconstriction in the renal circulation. Together with alterations in renal auto-regulation, a reduction in functional liver cell mass, and the development of cirrhotic cardiomyopathy, these processes result in a gradual increase in renal sodium and water retention. The presence of portal hypertension then preferentially localizes the excess fluid in the peritoneal cavity as ascites.

Figure 3.

Pathogenesis of ascites formation. EABV, effective arterial blood volume; GFR, glomerular filtration rate; Na, sodium; RAAS, rennin–angiotensin–aldosterone system; RBF, renal blood flow; SNS, sympathetic nervous system.

The management of ascites requires a stepwise approach, beginning with dietary sodium restriction and diuretic therapy, followed by second-line treatments once refractory ascites sets in.

Dietary sodium restriction

The underlying pathophysiology that leads to ascites formation in cirrhosis is renal sodium retention; therefore, the mainstay of treatment of ascites is to induce a negative sodium balance. This can be achieved by reducing the dietary sodium intake, as well as increasing the renal sodium output using a combination of diuretics.4 It is not uncommon for patients with ascites who are not on diuretics to have renal sodium excretion of < 20 mmol/day. Such a patient on a no-added-salt diet containing 130–150 mmol of sodium will retain at least 100 mmol of sodium/day, equivalent to the accumulation of 10 L of ascitic fluid in 2 weeks (100 mmol/day × 14 days ÷ 140 mmol/L = 10 L) (Table 2). The International Ascites Club has recommended a sodium intake of 88 mmol/day.5 This will require the use of special, low-sodium food items, and consultation with a dietician is usually required. Patients are more likely to adhere to a low-sodium diet if there is family support. In patients who normally consume a high-salt diet, the use of sodium restriction alone can lead to the reduction of ascites, especially if the urinary sodium excretion is > 78 mmol/day.6 If a patient who admits to adhering to a low-sodium diet and is still gaining weight rapidly, calculating the sodium balance (see Table 2) can often bring the message home. Salt substitutes usually contain high potassium contents, and can lead to hyperkalemia if patients are also on potassium-sparing diuretics. In the majority of cirrhotic patients with ascites, diuretics are usually required to induce a natriuresis.

Table 2.  Calculating the sodium balance
  1. Na, sodium.

Scenario IUrinary sodium excretion is 90 mmol/day
 Insensible sodium loss is 10 mmol/day
 Na intake = 88 mmol/day
 Na output = 100 mmol/day
 Na balance = (88–100) mmol/day = −12 mmol or −84 mmol/week
 Ascitic [Na] = 140 mmol/L (Same as serum [Na])
 Therefore fluid loss = −84 mmol / 140 mmol/L = −0.6 L
 Weight loss/week = 0.6 kg
Scenario IIUrinary sodium excretion is 0 mmol/day
 Insensible sodium loss is 10 mmol/day
 Na intake = 88 mmol/day
 Na output = 10 mmol/day
 Na balance = (88–10) mmol/day = +78 mmol
 Ascitic [Na] = 140 mmol/L (Same as serum [Na])
 Therefore fluid gain = +78 mmol / 140 mmol/L = 0.56 L
 Weight gain/day = 0.56 kg or Weight gain/week = 3.92 kg

Diuretic therapy

Diuretics block sodium reabsorption along the various nephron sites, thereby increasing renal sodium excretion. Water excretion then follows passively. It is customary to start diuretic therapy with an aldosterone antagonist, such as spironolactone, otherwise all the renal sodium that is not absorbed at the loop of Henle with the use of a loop diuretic alone will be reabsorbed at the distal tubule under the unopposed action of the high aldosterone levels. Spironolactone is usually administered at a start-up dose of 100 mg/day, and gradually increased up to 400 mg/day. The diuretic effect can be seen within 48 h, but the peak onset of action is 2 weeks, due to impaired metabolism in cirrhotics and a very long half-life of up to 5 days.5 Amiloride can be used instead of spironolactone, starting at 5 mg/day, and gradually increased to 20 mg/day. It has a shorter half-life, and therefore, a quicker onset of action, but is less effective than spironolactone, as shown in a randomized, controlled trial.7 Potassium canrenoate, another aldosterone antagonist, is popular in Europe, and has been shown to reduce the 1-year cumulative occurrence of ascites in cirrhosis.8 The starting dose is usually 200 mg/day, and gradually increased to 400 mg/day.

If the use of a distal diuretic is not producing the desired response, a loop diuretic, such as furosemide, can be added, starting at a dose of 40 mg/day, and gradually increased to 160 mg/day. The dose response curve of furosemide is sigmoidal. Therefore, once a maximum diuretic response is reached, further increases in furosemide dose will not increase the diuretic response. The most successful therapeutic regimen is the combination of a distal diuretic, such as spironolactone, and a loop diuretic, such as furosemide, beginning with 100 mg and 40 mg respectively, and increased in a step-wise fashion, preferably maintaining the same ratio of dosages, in order to maintain normal potassium levels.6

There have been discussions as to whether the simultaneous or sequential use of an aldosterone antagonist and a loop diuretic is more efficacious in the treatment of ascites. Santos et al.9 reported that both the sequential or combined use of diuretics was similar in terms of the diuretic response and diuretic-induced complications. However, Angeli et al. demonstrated in a randomized, controlled trial that treatment with combined diuretics could mobilize moderate ascites more rapidly than sequential diuretics, and was associated with less side-effects, including renal failure.10 The explanation for the difference in the findings could be that the patients in the study of Santos et al. were at a much earlier stage of ascites, with 60% of the patients enrolled at their first presentation of ascites, and at least 40% of them had normal supine levels of aldosterone.9 In the study of Angeli et al.,10 at least 70% of patients had recurrent ascites that required repeat paracenteses. Most had hyperaldosteronism, and many had reduced renal function. Therefore, it is reasonable to use sequential diuretics in patients with ascites at first appearance, and they will likely respond with a satisfactory natriuresis with ascites reduction. However, patients with recurrent ascites will be better served with combination diuretic therapy in order to reduce the time required to achieve a satisfactory diuretic response and to reduce the risk of hyperkalemia.

Patients on diuretic therapy need to be monitored regularly for electrolyte abnormalities, over-diuresis, and renal failure. As the volume of ascites that can be resorbed into the systemic circulation is approximately 400 mL/day,11 weight loss in excess of 0.5 kg/day means that there is reduction of the intravascular volume, thereby placing these patients at risk of the development of renal failure from over-diuresis. Patients with peripheral edema can tolerate more rapid fluid loss until the edema has resolved. Compliance with and response to sodium restriction and diuretics can be evaluated regularly by 24-h urine collection for sodium excretion. In situations where this is not feasible, a random urine sodium to a potassium ratio of > 1 predicts a > 78 mmol/day sodium excretion in 90% of patients.12 Non-compliance with a low-sodium diet is reflected by an adequate renal sodium excretion, but without any weight loss. A low renal sodium excretion necessitates increasing the diuretics doses as tolerated, up to the maximum recommended levels. When the combination of sodium restriction and diuretics is given to carefully-monitored patients, 90% of them can reduce or even eliminate their ascites with significant improvement in their quality of life.

Albumin

Albumin is a plasma protein that is most responsible for plasma colloid oncotic pressure. It is a negatively-charged molecule that attracts sodium and water, and therefore, it is a very good volume expander.13 In addition, it has many other functions, such as ligand binding, and antioxidant and endothelial stabilizing properties. Therefore, albumin seems the ideal solution to manage conditions where there is intravascular volume reduction, inflammation, or circulatory dysfunction. Albumin has been advocated as a treatment for many complications of cirrhosis and ascites, such as spontaneous bacterial peritonitis14 and HRS.15 As the basic pathophysiological process that leads to the development of ascites is a reduction of the effective arterial blood volume,16 it makes physiological sense to use albumin in the management of ascites, although this has been controversial.

In one randomized, controlled trial in cirrhotic patients with ascites, weekly infusions of 25 g of albumin added to standard diuretics was shown to produce a significantly better diuretic response compared to diuretics alone, including shorter hospital stay, lower probability of ascites reaccumulation, and a lower likelihood of readmission to hospital, but no effect on survival.17 In a later study by the same investigators, the use of 25 g/week albumin for 1 year, and thereafter, 25 g every 2 weeks for up to 120 months in patients with first-onset ascites, resulted in a significant increase in survival of 16 months and a significantly lower probability of ascites recurrence.18 The major drawback of chronic albumin use is its cost. For this reason, there is currently no standard recommendation to use albumin as an adjunct therapy to diuretics in the treatment of uncomplicated ascites.

Refractory ascites

Refractory ascites is defined as ascites that cannot be easily mobilized (< 1.5 kg weight loss/week), despite daily doses of 400 mg spironolactone or 30 mg amiloride plus 160 mg furosemide; and the patient must have been compliant with dietary sodium restriction of ≤ 90 mmol/day for ≥ 1 week.19 Patients who cannot tolerate diuretics because of the development of complications are defined as having diuretic-intractable ascites (Table 3).19 Because these patients are either unresponsive to or are intolerant of diuretics, second-line treatments, such as regular large-volume paracentesis (LVP) or the insertion of a transjugular intrahepatic portosystemic shunt (TIPS), are needed for the management of their ascites. All of these patients should also be considered for liver transplantation, unless there is a contraindication.

Table 3.  Diagnostic criteria for refractory ascites
  • Grading of ascites; Grade 1 = mild ascites only detectable by ultrasound examination; Grade 2 = moderate ascites that is manifest by moderate symmetrical distension of the abdomen; Grade 3 = large or gross ascites with marked abdominal distension.

  • Adapted from Salerno et al.19

1.Treatment duration: Patients must be on intensive diuretic therapy (spironolactone 400 mg/day and furosemide 160 mg/day) for at least 1 week and on a salt-restricted diet of less than 90 mmol/day or 5.2 g of salt/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 treatment.
 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.

LVP

Several large randomized, controlled trials have shown that LVP of 4–6 L is safer and more effective for the treatment of tense ascites than the use of high doses of diuretics.20–22 The incidence of systemic and hemodynamic disturbance, electrolyte abnormalities, renal impairment, and encephalopathy was lower in those treated with repeated LVP compared to diuretic therapy. Shorter duration of hospitalization was observed with LVP, but the rates of hospital readmission and survival were similar to those of diuretic therapy.20 Because LVP does not alter the pathogenetic mechanisms that lead to ascites formation, ascites will recur following a paracentesis.

The frequency and the volume of LVP can be determined from the patient's sodium intake. For a patient who is adherent to sodium restriction of 88 mmol/day, the weekly weight gain, and therefore ascites accumulation, should be < 4 L/week (Table 2), and this should be correspondingly less for patients whose sodium intake is less than 88 mmol/day. Therefore, a patient who is requesting a LVP of 10–12 L every week is obviously not adhering to a low-sodium diet. Counseling with a dietician is often helpful to reduce the sodium intake in order to make LVP more manageable for both the physician and the patient.

The next question is whether intravascular volume replacement is necessary following LVP. Reaccumulation of ascites following LVP can lead to a reduction in central circulatory volume, with potential for compromising systemic hemodynamics, a condition known as paracentesis-induced circulatory dysfunction (PICD), defined as an increase in plasma renin activity by > 50% of the preparacentesis level to a final value of > 4 ng/mL/h.23 This could lead to further activation of the already activated vasoconstrictor systems and place the patient at risk of the development of renal dysfunction. There are data to suggest that paracentesis of < 6  L can be safely performed without the use of volume expanders,24,25 thus the incidence of circulatory dysfunction is only 7% in paracenteses of < 6 L, and there is little, if any, clinical consequence.25 This is especially true in patients with peripheral edema, since the edema fluid can be reabsorbed to replenish the central circulation. In contrast, the use of total paracentesis was associated with the development of PICD in 37% of patients.23

There has been much debate about the use of volume expanders following every paracentesis, because PICD does not occur after every episode of LVP,26 nor does every case of PICD lead to the development of renal impairment.27 In one study, only 40% of patients who experienced PICD developed significant renal impairment, while 11% developed renal impairment, even without any evidence of circulatory dysfunction.23 Gines et al. not only advocated the use of plasma expanders following every paracentesis, they also demonstrated that the use of albumin was the most effective of all volume expanders to reduce the incidence of PICD.28 However, other studies have shown that synthetic plasma expanders are as effective as albumin in preventing hyponatremia and renal impairment following LVP.29,30 To support the use of albumin, a recent double-blind, randomized pilot study showed that the number of liver-related complications was significantly lower in patients who were infused with albumin compared with those infused with polygeline.31 Given the fact that albumin has not been shown to cause any harm in cirrhosis, the International Ascites Club recommends that, until further results are available, the infusion of albumin of 6–8 g is to be given per liter of ascitic fluid removed for LVP of > 5–6 L.19 A recent study from Toronto demonstrated that as long as the ascitic volume removed is less than 8 L, and the standard dose of albumin of 6–8 g/L of ascitic fluid removed is given, the development of PICD is not associated with any renal dysfunction.32

Although cirrhotic patients might have coagulopathy and thrombocytopenia, the incidence of clinically-significant intra-abdominal bleeding during an LVP is estimated to be ≈0.5%. Therefore, the routine use of fresh–frozen plasma or platelet concentrates is not recommended. Leakage of ascitic fluid through the puncture site is a relatively frequent complication. The Z-tract technique should reduce its occurrence. Ascites leakage post-LVP should be managed by placing a purse-string suture around the puncture site or by applying skin adhesive, and instructing the patient to lie with the puncture site uppermost.33 The use of a colostomy bag to contain the ascites leak should be discouraged because of the increased risk of infection.

TIPS

A TIPS functions like a side-to-side portocaval shunt, and is very effective in reducing portal pressure. As sinusoidal portal hypertension is one of the pathogenetic mechanisms of ascites formation in cirrhosis, it stands to reason that a successful TIPS insertion should be able to eliminate ascites. In addition, the successful insertion of TIPS returns a significant volume from the splanchnic circulation to the systemic circulation, thereby reducing the extent of underfilling of the effective arterial blood volume.34 Even in the absence of diuretics, increased sodium excretion begins after the first month following TIPS insertion. Thereafter, it increases further to culminate in a renal sodium excretion of approximately 100 mmol/day at 12 months.35 Patients will need to stay on a low-sodium diet in the post-TIPS period, or must take diuretics in order to facilitate ascites clearance. Within 6 months, complete resolution of ascites occurs in approximately two-thirds of patients, and a partial response in the other one-third. Further resolution can occur up to 12 months post-TIPS, with ultimately approximately 80% of patients completely clearing their ascites.

Recent results have shown that the presence of diastolic dysfunction, part of the cirrhotic cardiomyopathy syndrome,36 is associated with poor ascites clearance after TIPS.37 Successful TIPS placement with elimination of ascites improves renal function and35 nutritional status, and causes positive nitrogen balance,38 all leading to improved quality of life.

Five randomized, controlled trials have compared LVP versus TIPS as a treatment for ascites.39–43 All have showed that TIPS is much more effective than LVP in terms of the control of ascites, but at the expense of more episodes of hepatic encephalopathy.44 Other TIPS-related complications include those related to the procedure itself, and those related the presence of a shunt (Table 4).45,46 The recent advent of polytetrafluoroethylene (PTFE)-covered stents has significantly reduced the incidence of TIPS stenosis; this was seen in up to 70% of cases with bare stents in the first year after TIPS insertion,47 but with PTFE-covered stents, hepatic encephalopathy occurs in approximately 50% of patients in the first 2 years.48 This can easily be controlled with medical therapy, although occasionally, reducing the diameter of the stent is required for the management of the hepatic encephalopathy. The covered stents have the advantage of avoiding bile leakage into the stent lumen due to decreased abluminal porosity, and also a smoother internal lining, thereby permitting a more uniform endothelial growth.47,49,50

Table 4.  Complications related to transjugular intrahepatic portosystemic shunts (TIP)
Procedure relatedHemoperitoneum
Laceration of capsule
Laceration of vessels
Arteriovenous fistula
Hemobilia
Arrhythmia
Prosthesis relatedMigration of stent
Kinking
Hemolytic anemia
Infection of stent (endotipsitis)
TIPS dysfunctionThrombosis
Stenosis
Hepatic encephalopathyNew onset
Worsening
Progressive liver failureChild–Pugh score ≥ 12
Hepatocellular carcinoma 
CardiovascularArrhythmia
Cardiac failure

Until recently, TIPS has not been shown to provide a survival benefit in patients who receive it for the management of ascites.44 However, a recent meta-analysis using individual patient data from the four larger TIPS versus LVP randomized, controlled trials showed that TIPS does provide a survival advantage in the carefully-selected patients (Fig. 4).51 Therefore, patient selection is crucial to maximize the benefits of TIPS. In general, patients who are elderly, with a history of recurrent hepatic encephalopathy, or those with known cardiac dysfunction or pulmonary hypertension, as well as those with renal failure should be carefully assessed before being accepted for TIPS. In addition, TIPS insertion requires a patent portal vein for TIPS insertion to be technically feasible, and there should no structural abnormalities, such as multiple hepatic cysts. Finally, patients should be free of infections prior to TIPS insertion. If the presence of infection at another site colonizes the TIPS, which is not removable once inserted, the patient will become intermittently bacteremic, making it difficult to eradicate the infection.

Figure 4.

Survival of different subgroups of patients following transjugular intrahepatic portosystemic shunt insertion. (Adapted from Salerno et al.,51 with permission.)

The absolute and relative contraindications for TIPS insertion are shown in Table 5. Currently, a randomized, controlled trial is being conducted to assess the effect of TIPS versus LVP on the survival of patients at an earlier stage of the natural history of ascites, especially those with better liver function. If improved survival can be confirmed in certain subgroups of patients using TIPS, then the selection of patients for TIPS placement will have to take into consideration the patient's age, severity of liver dysfunction, and extent of circulatory dysfunction.

Table 5.  Contraindications for transjugular intrahepatic portosystemic shunt insertion for the management of refractory ascites
AbsoluteRelative
• Uncontrolled encephalopathy• > 70 years of age
• Congestive heart failure• Any infection, including dental sepsis
• Severe pulmonary hypertension• Non-compliance with sodium restriction
• Child–Pugh score ≥ 12• Hepatoma (especially if central)
• Multiple hepatic cysts• Portal vein thrombosis
• Unrelieved biliary obstruction 

Liver transplantation

All patients with refractory ascites should be assessed for liver transplantation, the only procedure which corrects both the impaired liver function and portal hypertension. Splanchnic and systemic hemodynamic abnormalities, which are pivotal in the pathogenesis of ascites formation, slowly return to normal after liver transplantation. Therefore, liver transplantation is the ideal treatment for advanced cirrhosis and ascites. However, with the introduction of the Model for End-Stage Liver Disease (MELD) score for the allocation of donor organs for liver transplantation,52 the presence of ascites no longer has any weighting in prioritizing patients for liver transplantation. It follows that patients with refractory ascites and low MELD scores, such as abstinent alcoholics or patients with inactive viral hepatitis, can remain on the liver transplant waiting list for an extended period of time without ever receiving a donor organ.

Various investigators have confirmed that mortality for patients on the liver transplant waiting list remains high (> 20% at 180 days), despite a lower MELD score of < 21, if the patient also has moderate ascites and hyponatremia.53–55 The more severe the ascites, the higher the waiting-list mortality.55 In fact, low-serum sodium and the presence of moderate ascites have been shown to be independent predictors of early pretransplant mortality in patients with a MELD score of < 21.53 As well, the Child–Pugh score, which includes ascites, seems to be a better index of prognosis than the MELD score in patients who have a MELD score of > 14.4.56 Efforts are now being made to modify the criteria for the allocation of donor organs, such as assigning points for persistent ascites and low-serum sodium in calculating the final score for organ allocation. This would improve the likelihood of patients with ascites receiving liver transplantation in a timely fashion.

Potential new treatments for ascites

Many investigators have been exploring other treatments for refractory ascites, because not all cases of refractory ascites are suitable for TIPS insertion, nor can every patient who receives a TIPS eliminate their ascites, and liver transplant is not available for all patients with advanced liver disease. The following is a summary of potentially-available agents.

Vasoconstrictors

Various vasoconstrictors have been assessed to determine whether improved splanchnic and systemic hemodynamics could lead to improved renal hemodynamics and increased renal sodium excretion, thereby reducing the ascites.

Midodrine is an alpha adrenergic receptor agonist that is approved for the treatment of postural hypotension. It is also popular in North America for the treatment of HRS. Its alpha agonist action results in an increase in mean arterial pressure in cirrhosis.57 In two small studies totaling 56 patients, the use of midodrine, either as a single oral dose,58 or given three times per day orally for 7 days,59 significantly improved renal hemodynamics, together with a significant increase in renal sodium excretion. In one of the studies,59 there was a significant correlation between the increase in systemic vascular resistance and an increase in glomerular filtration rate and enhanced renal sodium excretion. However, in patients who have normal systemic hemodynamics, the use of midodrine has not been shown to improve renal sodium excretion.60 With longer-term administration of midodrine (for 1 month in 8 patients with cirrhosis and refractory ascites), together with weekly albumin infusion and long-acting, slow-release octreotide, there was a significant reduction in plasma renin and aldosterone concentrations, but only a trend towards a reduction in the volume of ascites removed by paracentesis, without any effects on renal function.61

Terlipressin is a vasopressin analog that acts on the V1 receptor in the splanchnic vasculature to cause splanchnic vasoconstriction, thereby decreasing splanchnic inflow and lowering the portal pressure. The improvement in systemic hemodynamics has been successfully used in the treatment of HRS in cirrhosis. The role of terlipressin in the management of ascites has also been assessed in several studies. A single dose of 2 mg terlipressin given intravenously was effective in improving renal blood flow, the glomerular filtration rate, and renal sodium excretion in cirrhotics without renal dysfunction with (n = 8) or without (n = 11) ascites.62 The improvement in renal function correlated with decreased plasma norepinephrine and renin levels, and increased atrial natriuretic peptide concentrations. These results were confirmed in another study, which included 12 patients with cirrhosis and ascites, but without azotemia or hyponatremia.63 Systemic hemodynamics improved, associated with increases in creatinine clearance, diuresis and natriuresis.63

The positive results in these preliminary studies suggest that vasoconstrictors should be explored further as potential treatments for ascites. However, until the results of randomized, controlled trials are available, these agents cannot be regarded as standard of care in the management of refractory ascites.

Vasopressin V2 receptor antagonists

Vasopressin V2 receptor antagonists, or “vaptans”, are agents that compete with vasopressin for attachment onto the V2 receptors at the renal collecting duct to inhibit water reabsorption at that site, thereby inducing an aquaresis and reduced serum water content. The vaptans were first developed for the management of hyponatremia in patients with edematous states.64–66 It was observed in some of the above studies that the vaptans were also able to reduce the extent of ascites in cirrhotic patients.66 It is feasible that by maintaining serum sodium, the use of vaptans had permitted diuretics to be continued, thereby improving the control of ascites.

In a recent publication that reports on three large randomized, controlled trials involving 1200 patients with cirrhosis and ascites, the use of satavaptan either alone or in combination with diuretics was not shown to be clinically beneficial in the management of ascites. Further, in one of the three studies, it was associated with an increased mortality.67 Short-term studies involving other vaptans, such as M000268 or tolvaptan,69 have shown efficacy of these two vaptans in improving ascites. However, the study with M0002 only involved 15 patients for a total administration course of 2 weeks, while that using tolvaptan included 18 patients for a total of nine study days. Therefore, while the results are encouraging, it is not clear whether longer-term studies involving a larger cohort of patients with either M0002 or tolvaptan will confirm their efficacy in reducing ascites in cirrhosis. Currently there is no recommendation to use vaptans in the management of ascites.

ALFApump system

The ALFApump system (Sequana Medical AG, Zurich, Switzerland) is the latest investigational tool that is being developed for the management of ascites. It is a subcutaneously-implanted, battery-powered peritoneo-vesical shunt that pumps excess peritoneal fluid into the bladder where the patient can eliminate it through normal urination (Fig. 5). To date, 40 patients have received the device in a phase-3 clinical trial, which successfully removed 90% of the ascites (Dr Noel Johnson, pers. comm., 2011). With meticulous attention to aseptic techniques and the use of prophylactic antibiotics, the rate of infection has been no higher than what is expected in the cirrhotic population, despite the presence of the foreign body. With the device recently being approved in Europe, it is expected that this will significantly transform the management of ascites in the future, ultimately reducing the number of patients who require LVP as the mainstay of treatment for their ascites.

Figure 5.

Schematic picture of a peritoneo-vesical shunt in situ.

Conclusion

The medical management of ascites, including dietary sodium restriction and diuretic therapy, has not changed significantly for several decades. The development of TIPS two decades ago as a treatment for refractory ascites was regarded as the “new kid on the block”, but the emergence of many TIPS-associated complications quickly dampened the enthusiasm of clinicians caring for patients with refractory ascites, until the randomized, controlled trials and subsequent meta-analyses further refined the patient selection criteria for TIPS insertion. Currently, patients who are not suitable for TIPS insertion depend on regular LVP to control their ascites, while they await their turn for liver transplantation. With the recognition that the presence of ascites in patients with low MELD scores can negatively impact their prognosis, efforts are now being made to reassign points for the presence of ascites in calculating the priority for liver transplantation, so that patients with low MELD scores and ascites are not being disadvantaged.

Improved understanding of the pathophysiology of ascites formation provides possible novel options for the future, such as vasoconstrictor therapy that aims at correcting the abnormal physiology of cirrhosis. Technological advances mean that even in those patients whose only option is repeat LVP, it is possible in the future to have a device implanted so as to discharge the ascites through the urinary system. Preliminary data have suggested that survival might be improved with these newer treatments. The future will need to include randomized, controlled trials to evaluate and confirm the results of these recent studies to ultimately provide better treatments for ascites in patients with cirrhosis.

Ancillary