American Journal of Therapeutics 19, 121132 (2012)

Management of Refractory Ascites

Shashideep Singhal, MD,* Kiran K. Baikati, MD, Ibrahim I. Jabbour, MPH, MSIII,
and Sury Anand, MD

Ascites that does not respond or recurs after high-dose diuresis and sodium restriction should be
considered refractory ascites. As cirrhosis advances, the escaping fluid overwhelms the lymphatic
return. Decrease in renal plasma flow leads to increased sodium reabsorption at the proximal tubule
leading to decreased responsiveness to loop diuretics and mineralocorticoid antagonists, which work
distally. These complex hemodynamic alterations lead to refractory ascites. In refractory ascites, highdose diuresis (400 mg of spironolactone and 160 mg of furosemide) and sodium restriction
(,90 mmol/d) result in inadequate weight loss and sub optimal sodium excretion (,78 mmol/d).
Further use of diuretics is limited by complications such as encephalopathy, azotemia, renal
insufficiency, hyponatremia, and hyperkalemia. Therapy for refractory ascites is limited. The
available therapies are repeated large volume paracentesis (LVP), transjugular intrahepatic
portosystemic shunts, peritoneovenous shunts, investigational medical therapies, and liver transplantation. LVP with concomitant volume expanders is the initial treatment of choice. Transjugular
intrahepatic portosystemic seems to be superior to LVP in reducing the need for repeated
paracentesis and improves the quality of life. Several treatments that act at different steps in the
pathogenesis of ascites are investigational, and some show promising results. Splanchnic and
peripheral vasoconstrictors (Octreotide, Midodrine, and Terlipressin) increase effective arterial
volume and decrease activation of the reninangiotensin system with resultant increase in renal
sodium excretion. Clonidine when given with spironolactone has been shown to cause rapid
mobilization of ascites by significantly decreasing the sympathetic activity and reninaldosterone
levels. Natural aquaretics and synthetic V2 receptor antagonists (satavaptan) are being evaluated for
mobilization of ascites by increasing the excretion of solute-free water. Liver transplantation remains
the only definitive therapy for refractory ascites. Because refractory ascites is a poor prognostic sign,
liver transplantation should be considered and incorporated early in the treatment plan.
Keywords: ascites, cirrhosis, refractory, diuretics, TIPS

INTRODUCTION
Ascites is one of the most frequent complications of
cirrhosis. Almost half of all patients with compensated
liver cirrhosis develop ascites during 10 years of
observation.1 Portal hypertension and sodium retention are the 2 pathophysiologic hallmarks of ascites.24
Most patients respond to salt restriction and diuretics;
Department of Gastroenterology, The Brooklyn Hospital Center,
Brooklyn, NY.
The authors have no conflicts of interest to declare.
*Address for correspondence: Department of Gastroenterology, The
Brooklyn Hospital Center, 121 Dekalb Ave, Brooklyn, New York,
11105. E-mail: sdsinghal@gmail.com
10752765 2012 Lippincott Williams & Wilkins

however, each year 10% of patients develop refractory

ascites. Refractoriness develops for either 1 of 2 reasons,
both of which are related to treatment with diuretics.
First, unresponsiveness to diuretics may develop due
to advanced cirrhosis and hemodynamic changes in
the splanchnic and systemic circulations. Alternatively,
the diuretics may directly induce complications,
which lead to refractoriness.59 Refractory ascites
is diagnosed after excluding potential causes of uncontrolled ascites: peritoneal carcinomatosis, nephrogenic
ascites, hepatic vein thrombosis, noncompliance to diet
and medications, overdiuresis, and concurrent use
of non-steroidal anti-inflammatory drugs (NSAIDs).
Refractory ascites is a poor prognostic indicator.
The probability of survival in cirrhotic patients who
develop ascites is 85% and 56% at 1 and 5 years,
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respectively. In patients who become resistant to

diuretics, the probability of survival decreases to 50%
at 2 years.10,11 Furthermore, life expectancy decreases
to 6 months in patients with a urinary sodium excretion
,10 mEq/d.12 Because refractory ascites is an ominous
prognostic factor, referral for liver transplantation
should be done as soon as it is diagnosed. The treatment options currently available for refractory ascites
include large volume paracentesis (LVP), transjugular
intrahepatic portosystemic shunt (TIPS), peritoneovenous shunts, and liver transplantation.13

DEFINITIONS1416
Diuretic-resistant ascitesFailure to mobilize or early
recurrence of ascites, which cannot be prevented
because of a lack of response to salt restricted diet
and diuretic treatment.
Diuretic-intractable ascitesFailure to mobilize or
early recurrence of ascites, which cannot be prevented
because of the diuretic induced complications that
prevent the use of diuretics.
Lack of responseMean weight loss ,0.8 kg per
4 days and urinary sodium output less than the sodium
intake.
Duration of treatmentPatients must be on intensive
diuretic therapy (Spiranolactone 400 mg/d and Furosemide 160 mg/d) for at least 1 week and on a salt
restricted diet of ,90 mmol/d.
Early ascites recurrenceReappearance of grade 2 or
grade 3 ascites within 4 weeks of initial mobilization
with the exception of recurrence in 23 days of paracentesis in patients with severe ascites and peripheral
edema because it represents a shift of interstitial fluid to
the intraperitoneal space.
Diuretic-induced complications are as follows:
Diuretic-induced hepatic encephalopathy is the development of hepatic encephalopathy in the absence of
any other precipitating factor.
Diuretic-induced renal impairment is an increase of
serum creatinine by .100% to a value .2 mg/dL in
patients with ascites responding to treatment.
Diuretic-induced hyponatremia is defined as a decrease
of serum sodium by .10 mEq/L to a serum sodium
of ,125 mEq/L.
Diuretic-induced hypokalemia and hyperkalemia are
defined as a change in serum potassium to ,3 or
.6 mEq/L, respectively.

PATHOGENESIS
Currently, the most accepted mechanism of ascites
formation is forward theory (underfilling).17 The 2 main
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Singhal et al

pathogenetic mechanisms, which have synergestic

roles, are portal hypertension and sodium retention.24 An increased resistance to portal flow at the
level of the sinusoids leads to the development of
sinusoidal hypertension and increased transvascular
hydrostatic pressure that is transmitted back to
splanchnic capillaries. Shear stress in the splanchnic
capillaries and some unknown mechanisms cause the
release of local and systemic vasodilators. As a result,
there is splanchnic arterial vasodilation and pooling of
blood in the splanchnic circulation.2,3,1820 Overall,
the result is systemic vascular underfilling, which
activates sodium retaining neurohumoral mechanisms
to refill the dilated vascular bed.2123 The neurohumoral mechanisms include the sympathetic nervous
system (SNS), the reninangiotensinaldosterone system (RAA), and the nonosmotic release of vasopressin
(also known as anti diuretic hormone ADH). The
consequence of altered hemodynamics is a continuous
escape of fluid into the interstitial space.
Pathogenesis of refractory ascites (Figure 1): Initially,
the shift of fluid is compensated for by an increase in
lymphatic drainage. However, as cirrhosis advances
the escaping fluid overwhelms the lymphatic return
and fluid accumulates in the peritoneal cavity.24,25
RAA and vasopressin release are further activated in
advanced cirrhosis leading to sodium and water
retention, which further perpetuates the ascites. The
inadequacy of the increased cardiac output to meet
the demands of the changed hemodynamics results in
renal vasoconstriction. Decreases in renal plasma flow
and glomerular filtration rate lead to increased sodium
reabsorption at the proximal convoluted tubule with
less delivery to distal portions, where loop diuretics
and mineralocorticoid antagonists act. This leads to
refractory ascites. In addition, in advanced cirrhosis
there is an impaired responsiveness to vasoconstrictors
secondary to changes in receptor affinity, downregulation of receptors and postreceptor defects related to
increased expression of nitrous oxide.2628 The hypovolemic effects of diuretics also contribute to the
complications, precluding the use of effective dosage
diuretics.

EVALUATION
Exclusion of other causes
Greater than 5% of patients may have more than one
etiology. Conditions that induce transient or apparent
refractoriness to diuretics, and causes of ascites that are
not responsive to diuretics, should be excluded to
diagnose refractory ascites (Figure 2).
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123

FIGURE 1. Pathogenesis of refractory ascites.

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Singhal et al

FIGURE 2. Diagnostic algorithm for refractory ascites.

Conditions that worsen previously controlled ascites

and/or present as refractory ascites such as peritoneal
carcinomatosis, hepatic venous thrombosis, and nephrogenic ascites should be ruled out.29 Ultrasound with
portal vein doppler and serum alpha-fetoprotein
should be done in these patients (Table 1).30
Conditions that induce transient refractoriness to
diuretics include volume depletion (resulting in pre
renal failure) most commonly by inappropriate diuretic
therapy, vomiting, diarrhea, spontaneous bacterial peritonitis (SBP), and bleeding. Renal injury also induces
transient refractoriness both on its own and/or in
combination with the conditions previously mentioned.
Common offending agents include NSAIDs, nephrotoxic
drugs, and angiotensin-converting enzyme inhibitors.3134
Diet and medication noncompliance are important
considerations in a patient with poorly controlled
ascites. Dietary compliance can be assessed by the
urinary sodium excretion.
American Journal of Therapeutics (2012) 19(2)

Twenty-four-hour urinary sodium excretion

Twenty-four hour urinary sodium excretion is more
accurate surrogate for assessing dietary compliance but
more cumbersome for the patient and staff. Patients
who gain weight despite excreting .78 mEq sodium
per day are likely noncompliant with diet.16 Its accuracy is measured in regards to the urinary creatinine,
which is 15 mgkg21d21 in males and 10 mgkg21d21
in females.35 However, this may not be very accurate
in patients with advanced cirrhosis due to muscular
wasting and lower creatinine excretion.36,37
Spot urine sodium excretion
Spot urine sodium excretion can also be used but it is
not as accurate as the 24-hour measurement because
the rate of urine sodium excretion is not uniform
throughout the day. It is only useful if .100 mmol/L
or equal to zero mmol/L. Values .100 mmol/L are
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125

FIGURE 3. Management approach for refractory ascites.

interpreted as either an adequate response to diuretics

or an indication of dietary non-compliance. A value
of 0 mmol/L indicates low sodium excretion and lack
of diuretic response. Values falling between 0 and 100
mmol/L are indeterminate and not clinically useful.13
Random urinary sodium:potassium ratio
The random urinary sodium to potassium ratio is
a simple test for the patient and staff. Its accuracy is
reported to be 86%90%.38 A ratio of .1 is equivalent
to a 24-hour urinary sodium excretion of .78 mEq/L.
Furosemide-induced natriuresis
Furosemide-induced natriuresis is an alternative diagnostic tool for patients who are responsive to diuretics.
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Refractory ascites may be diagnosed if an 80-mg

intravenous injection of furosemide causes ,50 mEq of
urinary sodium excretion in 8 hours. This method
allows rapid identification of patients who are responsive to diuretics.39,40 Despite this, safety concerns
preclude its repeated use because intravenous furosemide may cause azotemia. This diagnostic approach
should be avoided until its safety is evaluated in
randomized controlled trials.

TREATMENT
Currently, the treatment options available for refractory ascites are shown in Figure 3: LVP with albumin
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Singhal et al

infusions, TIPS, peritoneovenous shunts (surgical

option), and liver transplantation.13

$ 3 mg/dL and Child Score $9) are likely to benefit

from long-term antibiotic prophylaxis.51,52

Large volume paracentesis

Complications

LVP is the firstline treatment for refractory ascites. It

improves quality of life and decreases the risk of
variceal bleeding.41,42 One drawback is that LVP has no
role in modifying the pathology of ascites; hence, both
physician and patient should anticipate recurrence.
A reasonable interval between LVP sessions is
2 weeks.13,43 The major determinant of LVP frequency
is dietary sodium compliance. Other determinants
are the body habitus of the patient, tolerability of
abdominal distention, urinary sodium excretion, and
the rate of ascite formation.42 If the urinary sodium
excretion is .30 mEq/d, diuretics may be used to
reduce the frequency of LVP. However, diuretics should
be discontinued if refractoriness is due to complications
induced by the drugs.4447 Total paracentesis can be
done as an outpatient procedure and is preferred to
multiple therapeutic paracentesis because of less
frequent complications related to needle insertion. This
also avoids fluid leakage as no fluid remains in the
abdominal cavity.

BleedingThe risk of hematoma formation is 1%. The

risk of intraperitoneal hematoma or iatrogenic infection
is 1 in 1000. Bleeding risk increases in patients with renal
failure due to dysfunctional platelets. Paracentesis can
safely be performed in patients with an international
normalized ratio as high as 8.7 and platelets ,19,000.53
Routine infusion of platelets and fresh frozen plasma
before paracentesis is not recommended. In view of the
bleeding risk, paracentesis should be avoided in
disseminated intravascular anticoagulation with clinically evident fibrinolysis.54
Leakage of fluid from the paracentesis siteThis could
be prevented by preferring total LVP to multiple LVP,
Z-tract technique,55,56 and instructing the patient to lie
on the opposite side of where the fluid was drained.
InfectionFrequent LVP results in the depletion of
protein and complement, which may predispose to
infection.57
Paracentesis-induced circulatory dysfunction (PICD)
PICD is defined as an increase in plasma renin activity
of .50% over baseline up to a value .4 ng mL21h21
on day 6 of paracentesis.5860 Immediately after paracentesis, the decrease in intraabdominal pressure
results in an increased venous return that increases
cardiac output and suppresses RAA and SNS.58 The
hyperkinetic circulation leads to shear stress on the
vessels with pooling of blood in the splanchnic and
systemic circulations. The consequence is decreased
effective arterial blood volume and marked activation
of RAA and SNS to levels above the baseline.61 Even if
asymptomatic, PICD may persist for months and is
associated with adverse events such as hepatorenal
syndrome, hyponatremia, and increased rate of recurrent ascites.62 PICD severity is directly dependent
on the amount of fluid removed and inversely
correlated with survival.62 The incidence of PICD
decreases from 80% to 15% when albumin infusions are
used postparacentesis.63 Although the pathogenetic
mechanism behind PICD most likely involves accentuation of splanchnic and systemic vasodilation (and
not intravascular volume depletion) it is still advisable
to give albumin infusions if .5 L are removed.61
Albumin is given to avoid any adverse events
associated with PICD, despite there being an absence
of large randomized controlled trials showing its
survival benefit. Alternative plasma expanders such
as dextran, hydroxyethyl starch, and normal saline can
also be used but with no significant survival advantage
as compared with albumin.64 Hydroxyethyl starch
increases portal hypertension further by depositing in

Spontaneous bacterial peritonitis evaluation and

prophylaxis
The prevalence of SBP (0%3.5%) in outpatient therapeutic paracentesis is low.48 Despite this, ascitic fluid
polymorphonuclear cell count (PMNC) should be
done in every patient, even if asymptomatic, during
every paracentesis session. If symptomatic with fever,
abdominal pain, hepatic encephalopathy, acidosis,
azotemia, hypotension, or hypothermia, then the
patient should be hospitalized and a diagnostic
paracentesis should be performed. Blood and fluid
cultures should be sent and empiric antibiotic therapy
started. It is appropriate to give either a third
generation cephalosporin (cefotaxime 2 g every 8
hours or ceftriaxone 3 g/d) or amoxicillin/clauvulanate (amoxycillin/clavulanate 1 g TID) for at least 5
days and to repeat paracentesis in 48 hours to
document a PMNC that is .25% decreased. Antibiotics should be changed based on culture if there is
no PMNC decrease at 48 hours. Albumin (1.5 g/kg
body weight per day on day 1 and 1 g per kg body
weight per day on day 3) in addition to antibiotics
are given to patients with a serum bilirubin .4, BUN
.30 mg/dL, and creatinine .1 mg/dL. This combination prevents deterioration in renal function and
also increases survival.49,50 Patients with a history of
SBP, ascitic fluid protein ,1 g/dL, serum creatinine
.1.2 g/dL or BUN .25 mg/dL), serum sodium
#130 mEq/L, and severe liver disease (bilirubin
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Table 1. Differential diagnosis of refractory ascites.

Mimickers of refractory ascites
Peritoneal carcinomatosis
Nephrogenic ascites in end-stage renal
disease
Hepatic vein thrombosis
Diet and medication non-compliance

Transient refractoriness to diuretics

NSAIDS, ACE inhibitors, nephrotoxic drugsaminoglycosides
Overdiuresis
Inappropriate diuretic regimen
Prerenal failurevomiting, bleeding, diarrhea, bacterial infections, SBP
Dietary/medication noncompliance

Kupffer cells. Because the pathogenesis of PICD may be

due to accentuated splanchnic vasodilation, a few
studies investigated the use of terlipressin, midodrine,
and noradrenaline but larger studies are required to
establish their efficacy.6570
Transjugular intrahepatic portosystemic shunt
TIPS is a side to side portocaval shunt that establishes
a communication between the hepatic vein and portal
vein to relieve the hepatic venous pressure gradient.71
It is a nonsurgical procedure performed by interventional radiologists under local anesthesia. TIPS decompresses the portal circulation and also decreases the
portocaval gradient and the portal venous pressure,
which is an essential determinant of ascites formation
(hepatic venous pressure gradient .12 mm Hg).60,72, 73
TIPS also increases venous return and cardiac output
by shunting blood from dilated splanchnic vessels to
the systemic circulation and ameliorates the activation
of RAA and SNS.60
TIPS is highly effective in controlling ascites because
it partially resolves the pathogenesis of ascites formation. It also improves the quality of life, nutritional
status, and renal function. Increased excretion of
urinary sodium and urine volume are signs of the
latter. Improved serum creatinine is observed in 36

months.74,75 By improving renal function, TIPS may

convert a patient from refractory to responsive to
diuretics. Once this occurs, diuretics and salt restriction
can be initiated to reduce the frequency of paracentesis
sessions.
Few randomized controlled trials7680 have compared the effects of TIPS with LVP. The comparison of
TIPS vs. LVP is shown in Table 2. Consensus of the
studies shows TIPS to be superior to LVP in controlling ascites, and improving renal function, quality
of life, nutritional status, and positive nitrogen
balance. Among the studies, only one showed a
significant survival benefit for TIPS when compared
with LVP. However, it should be noted that this
study was not limited only to refractory ascites
patients with advanced liver disease but also
included recidivant ascites patients. The frequency
of hospitalizations and hepatic encephalopathy was
similar in both groups but the encephalopathy seen in
the TIPS group was generally more severe. Therefore,
LVP remains the firstline treatment for refractory
ascites considering the severity of complications
associated with TIPS.
[Recidivant ascites recurs at least on 3 occasions
within 1 year despite prescription of dietary sodium
restriction and adequate diuretic dosage5].

Table 2. TIPS vs TAPS (LVP).

Large volume paracentesis
Local therapy, with no role in the modification
of pathogenesis.
Increased risk for infection due to depletion of
protein and complement.
Lesser incidence of encephalopathy and less
severe when compared with TIPS.
Outpatient procedure.

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TIPS
TIPS partially modifies the pathogenesis of ascites.
Decreased frequency of paracentesis.
Improves renal function and converts diuretic resistant
ascites to diuretic sensitive
Increased quality of life, increased nutritional status.
Decreased frequency of paracentesis.
Decreased rate of hospitalizations.
Increased severity of encephalopathy.
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Singhal et al

Complications

Liver transplantation

Technical complicationsProcedure related mortality

rate is 1%2%.81 Most commonly deaths are due to
hemoperitoneum, hemobilia, hemolysis, and sepsis.
Procedure related complication rate is around 9%.
Intraperitoneal hemorrhage and acute renal failure are
the most frequent complications.82
Hepatic encephalopathyHepatic encephalopathy develops 10 days after TIPS insertion (90.91) and slowly
declines by 6 months because of shunt stenosis, which
is associated with increased age, Child-PUGH score
.11, Model for End Stage Liver Disease score .18,
and a history of hepatic encephalopathy before TIPS
insertion.83,84.
Shunt occlusionShunt occlusion occurs in 22%50%
of patients with TIPS and incidence increases with
time. Doppler ultrasonography every 3 months and
venogram every year are recommended.16
HemolysisHemolysis occurs in 10% of patients.
Most cases are self-limited and spontaneously resolved
after 812 weeks once the pseudointima is developed.85,86
InfectionInfection is a rare complication occurring
in 1.5% of the patients.
Liver failurePatients with advanced liver disease
(MELD score .18 or Child PUGH score .11) may
develop acute liver failure immediately after TIPS
insertion. The mechanism is ischemia secondary to
shunting of the blood supply from the portal circulation directly to the systemic circulation.87,88
Renal failureAlthough TIPS improves renal function, 4.3% of patients develop renal failure secondary
to worsening systemic vasodilation after TIPS insertion.

Liver transplantation is the definitive therapy for

refractory ascites. Although portal hypertension is
reversed immediately and completely after transplantation it still takes 36 months for the ascites to resolve.
The reasons for this delay are not yet understood.11
Refractory ascites being an ominous prognostic factor,
patients should immediately be evaluated for liver
transplantation. MELD scores are used to prioritize
patients despite controversy over its accuracy in
assessing patients for transplantation. This is highlighted by the fact that some patients with refractory
ascites have a poor prognosis despite a low MELD
score.15,93 MELD scores include serum creatinine,
international normalized ratio, and bilirubin. A few
patients with refractory ascites have a near normal
serum creatinine despite having a low glomerular
filtration rate.30 The Modified MELD score was developed by adding serum sodium to improve its
accuracy.9496 Even so, serum sodium is altered by
diuretic usage,15 so the Modified MELD is not entirely
free of error. Studies are needed to evaluate the
superiority of Modified MELD over MELD for
prioritizing patients for liver transplantation.

Surgical options
A peritoneovenous shunt drains ascitic fluid from the
peritoneal cavity into the internal jugular vein.
Peritoneo-venous shunts (Leveen or Denver shunts)
should be considered for patients who (1) are not
candidates for TIPS and Liver transplantation, (2) have
lots of abdominal scarring making frequent paracentesis difficult, and (3) live far from a physician who
is willing to perform or capable of performing paracentesis.89 It is associated with many serious complications such as hepatic encephalopathy, small bowel
obstruction, bacteremia, and volume overload leading
to variceal bleeding. This option shows no significant
survival benefit.90 Occlusion rate is high and makes
future TIPS insertion and liver transplantation difficult.
In comparison to TIPS, the mortality rate is significantly higher (12%39%). The rate of hepatic encephalopathy is .50%, which is also .TIPS.91 Shunts that
drain peritoneal fluid into the bladder are under
investigation.92
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Experimental treatment options

Aquaretics
Aquaretics are vasopressin receptor antagonists that
act at the distal tubule of the kidney to increase
excretion of solute-free water. Lixivaptan and satavaptan are selective only for V2 receptors and are available
in oral forms. One study reported significant decrease
in abdominal girth and more weight reduction with
satavaptan, but because the follow-up duration was
very short (14 days), more studies are needed to
validate this drug.97
Vasoconstrictors
Vasoconstrictors improve systemic and splanchnic
vasodilation and may improve the natriuretic response of kidneys to diuretics. One study using
terlipressin on 15 patients showed significant decreases in renin and plasma norepinephrine levels. It
also improved urinary sodium excretion.98 Octreotide
causes splanchnic vasoconstriction by decreasing
glucagon secretion. It also inhibits the release of renin
and aldosterone. One case report showed improvement in urinary sodium excretion in 2 patients with
refractory ascites with administration of octreotide.99
Midodrine, an alpha-1 agonist, also improves urinary
sodium excretion and urine volume by increasing the
mean arterial blood pressure and decreasing renin and
aldosterone.100
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Refractory Ascites

Clonidine
Clonidine, a centrally acting alpha-2 agonist, improves
renal natriuretic function and helps in mobilization
of ascites by decreasing SNS and RAA activation.101
In 1 study of 32 alcoholic patients with liver cirrhosis,
spironolactone and clonidine were used as combination treatment. This combination of drugs significantly
increased natriuresis, decreased body weight, and
decreased plasma renin and aldosterone.102 A pilot
randomized trial comparing paracentesis plus albumin
versus clonidine plus spironolactone in patients with
refractory ascites and plasma norepinephrine .300
pg/mL demonstrated fewer hospitalizations in the
clonidine plus spironolactone group.103,104
Chronic albumin infusion
An unblinded randomized controlled trial in newonset ascites patients, with weekly infusions of 25 g
albumin for 1 year and then biweekly infusions
after 1 year, demonstrated increased survival when
compared to diuretics alone.105 A retrospective study
also demonstrated the efficacy of 50 g of albumin
infusions every week in reducing body weight in
refractory ascites.105,106 Due to the high cost of
albumin, such infusions are considered experimental
until further studies prove both their efficacy and cost
effectiveness.

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