Management of Adult Patients With Ascites Caused by Cirrhosis

1. AASLD Practice Guidelines
Management of Adult Patients With Ascites Caused by Cirrhosis
BRUCE A. RUNYON
Ascites is the most common of the major complications of
cirrhosis. The development of ascites is an important
landmark in the natural history of cirrhosis and has been
proposed as an indication for liver transplantation. The
initial evaluation of a patient with ascites should include a
history, physical evaluation, and abdominal paracentesis
with ascitic fluid analysis. Treatment should consist of
abstinence from alcohol, sodium restricted diet, and diuret-
ics. This regimen is effective in Ϸ90% of patients. The
treatment options for the diuretic-resistant patients include
serial therapeutic paracenteses, liver transplantation, and
peritoneovenous shunting. (HEPATOLOGY 1998;27;264-272.)
PREAMBLE
These guidelines provide a data-supported approach to the
care of patients with ascites. They are based on the following:
1) a formal review and analysis of the published world
literature (1,045 papers) on ascites (Medline Search from
1966-1996, search terms included ascites, diet therapy, drug
therapy, radiotherapy, surgery, and therapy); 2) the American
College of Physician’s Manual for Assessing Health Practices
and Designing Practice Guidelines1; and 3) several published
and draft guidelines, including the American Association for
the Study of Liver Diseases’ Policy Statement on Development
and Use of Practice Guidelines and American Gastroenterologi-
cal Association’s Policy Statement on Guidelines2; and 4) 15
years of experience on the part of the author in the clinical
and laboratory investigations of and care for patients with
this problem.
These guidelines, intended for use by physicians, suggest
preferable approaches to the diagnostic, therapeutic, and
preventative aspects of care. These guidelines are intended to
be flexible, in contrast with ‘‘standards of care,’’ which are
inflexible policies to be followed in almost every case.1
Furthermore, these guidelines were developed for the care
of adult patients with clinically detectable ascites. Although
the general approach may be applicable to children, the
pediatric data base is much smaller and there may be
unanticipated differences between adults and children. Pa-
tients with ascites that is detected by imaging modalities
alone, but not yet clinically evident, are not included because
of the lack of published information regarding the natural
history of this entity.
Specific recommendations are based on relevant published
information. In an attempt to standardize recommendations,
the Practice Guidelines Committee of the American Associa-
tion for the Study of Liver Diseases modified the categories of
the Infectious Diseases Society of America’s Quality Stan-
dards.3 These categories are reported with each recommenda-
tion, using the letters A through E to determine the strength
of recommendation and roman numerals I through III to
determine quality of evidence upon which recommendations
are based, as follows: A, survival benefit; B, improved
diagnosis; C, improvement in quality of life; D, relevant
pathophysiologic parameters improved; E, impacts cost of
health care; I, evidence from multiple well-designed random-
ized controlled trials, each involving a number of participants
to be of sufficient statistical power; II, evidence from at least
one large, well-designed clinical trial with or without random-
ization from cohort or case-control analytic studies or from
well designed meta-analysis; III, evidence based on clinical
experience, descriptive studies, or reports of expert commit-
tees; and IV, not rated.
Background
Cirrhosis was the eleventh leading cause of death, accord-
ing to the 1994 Morbidity and Mortality Weekly Report.4 It is
estimated that there are 3 million Americans with cirrhosis.
Ascites is the most common of the three major complications
of cirrhosis; the other complications include hepatic encepha-
lopathy and variceal hemorrhage.5 Approximately 50% of
patients with ‘‘compensated’’ cirrhosis, i.e., without having
developed one of these complications, develop ascites during
10 years of observation.5 The development of fluid retention
in the setting of cirrhosis is an important landmark in the
natural history of chronic liver disease. Approximately 50%
of patients with ascites succumb in two years,6 which has led
to inclusion of ascites as one of the indications for initiating
evaluation for liver transplantation.
Evaluation
History. Most patients (Ϸ80%) with ascites in the United
States have cirrhosis.7 There is a nonhepatic cause of fluid
retention in about 20% of patients with ascites. Successful
treatment depends on an accurate diagnosis of the cause of
ascites, e.g., peritoneal carcinomatosis does not respond to
diuretic therapy.8 Patients with ascites should be questioned
about risk factors for liver disease, including alcohol, intrave-
nous and recreational drug use, transfusions, homosexuality,
acupuncture, tattoos, ear-piercing, country of origin, family
history, history of jaundice or hepatitis, etc. Past history of
cancer, heart failure, or tuberculosis is also relevant.
Physical Examination. The presence of a full, bulging abdo-
men should lead to percussion of the flanks. If the amount of
Abbreviations: PMN, polymorphonuclear; SBP, spontaneous bacterial peritonitis.
From the Loma Linda Transplantation Institute, Loma Linda, CA.
Received August 14, 1997; accepted October 21, 1997.
Written under the Auspices of The American Association for the Study of Liver
Diseases Practice Guidelines Committee.
Address reprint requests to: Bruce A. Runyon, M.D., Director of Hepatology, Medical
Director of Liver Transplantation, Loma Linda Transplantation Institute, 11234
Anderson Street, Room 1405, PO Box 2000, Loma Linda, CA 92354.
Fax: (909) 478-4110.
Copyright ௠ 1998 by the American Association for the Study of Liver Diseases.
1270-9139/98/2701-0039$3.00/0
264

2. flank dullness is greater than usual, i.e., if the percussed
air-fluid level is higher than that normally found on the
lateral aspect of the abdomen with the patient supine, then
‘‘shifting’’ should be checked for. If there is no flank dullness,
there is no reason to check for shifting. Approximately 1,500
mL of fluid must be present to detect dullness.9 If flank
dullness is not present, the patient has less than a 10% chance
of having ascites.9
An abdominal ultrasound may be required to determine
with certainty if fluid is present. Ultrasonography can detect
as little as 100 mL of fluid in the abdomen.10
Diagnosis
The diagnosis of recent onset ascites is suspected on the
basis of the history and physical examination and is usually
confirmed by successful abdominal paracentesis and/or ultra-
sound. The diagnosis of the cause of ascites formation is
based on the results of the history, of a physical, and of ascitic
fluid analysis. In general, few other tests are required. Other
radiologic or endoscopic procedures usually provide little
information in the initial evaluation of the patient with
ascites.
Abdominal Paracentesis. Abdominal paracentesis with appro-
priate ascitic fluid analysis is probably the most rapid and
cost-effective method of diagnosing the cause of ascites.11
Also, in view of the 10% to 27% prevalence of ascitic fluid
infection at the time of admission to the hospital, an
admission surveillance tap may detect unexpected infec-
tion.12
Although older published series have reported a relatively
high morbidity, and even mortality, when trocars were used
for paracentesis, more recent studies regarding paracentesis
complications in patients with ascites documented no deaths
or infections caused by the paracentesis.13,14 Complications
have been reported in only about 1% of patients (abdominal
wall hematomas), despite the fact that 71% of the patients
had an abnormal prothrombin time.13 Although more serious
complications (hemoperitoneum or bowel entry by the
paracentesis needle) occur, they are unusual enough (Ͻ
1/1,000 paracenteses) that they should not deter performance
of this procedure. It is the practice of some physicians to give
blood products, such as fresh frozen plasma and/or platelets,
routinely before paracentesis in cirrhotics with coagulopathy.
This policy is not data-supported. Because a transfusion-
requiring hematoma develops in only Ϸ1% of patients who
undergo paracentesis without prophylactic transfusions of
plasma or platelets, approximately 140 U of fresh frozen
plasma and/or platelets must be administered to prevent the
transfusion of Ϸ2 U of red cells. The risks and costs of
prophylactic transfusions exceed the benefit.
There are few contra-indications to paracentesis. Although
coagulopathy is a potential contraindication, most patients
with cirrhotic ascites have coagulopathy. If mild coagulopa-
thy were viewed as a contra-indication to paracentesis, few
cirrhotics would undergo this procedure. Coagulopathy should
preclude paracentesis only when there is clinically-evident
fibrinolysis or clinically-evident disseminated intravascular
coagulation.13,14 These conditions occur in less than 1 of
1,000 procedures. There is no data-supported cutoff for
coagulation parameters beyond which paracentesis should be
avoided.13,14
Recommendations
Abdominal paracentesis should be performed and ascitic
fluid should be obtained from inpatients and outpatients with
clinically-apparent new onset ascites. Bleeding is sufficiently
uncommon to preclude the need for prophylactic fresh frozen
plasma or platelets. (Rating, II BE.)
ASCITIC FLUID ANALYSIS
Analysis
Although future studies are required to determine an
optimal testing strategy, meanwhile, an algorithm approach
seems preferable to ordering a large number of tests on most
specimens. If uncomplicated cirrhotic ascites is suspected,
only screening tests, e.g., cell count and differential and
albumin concentration, are performed on the initial speci-
men. If the results of these tests are unexpectedly abnormal,
further testing can be performed on another ascitic fluid
sample. However, as most specimens consist of uncompli-
cated cirrhotic ascites, no further testing will be needed in the
majority of patients.
If ascitic fluid infection is suspected, cell count and
differential, albumin concentration, and bacterial culture in
blood culture bottles are performed. Additional testing, e.g.,
total protein, lactate dehydrogenase, and glucose to assist in
differentiating spontaneous from secondary bacterial peritoni-
tis, can be performed on the initial specimen based on clinical
judgement.12
The serum-ascites albumin gradient has been proved in
prospective studies to categorize ascites better than the
total-protein based exudate/transudate concept and than the
modified pleural fluid exudate/trandudate criteria.15-17 Calcu-
lating the serum-ascites albumin gradient involves measuring
the albumin concentration of serum and ascitic fluid speci-
mens and subtracting the ascitic fluid value from the serum
value. With approximately 97% accuracy, a serum-ascites
albumin gradient of H1.1 g/dL (11 g/L) indicates that the
patient has portal hypertension.15 Conversely, a serum-ascites
albumin gradient of Ͻ1.1 g/dL (11 g/L) with Ϸ97% accuracy
that the patient does not have portal hypertension.
Patients undergoing serial outpatient therapeutic paracen-
teses probably should be tested only for cell count and
differential; bacterial culture is not necessary in asymptom-
atic patients.18
The most expensive tests are the cytology and smear and
culture for mycobacteria; these tests should probably be
ordered only when there is a high pretest probability of
occurrence of the disease under consideration. Only Ϸ7% of
ascitic fluid cytologies are positive and only in the setting of
peritoneal carcinomatosis.19 These patients usually have a
history of a breast, colon, gastric, or pancreatic primary. The
sensitivity of smear for mycobacteria is Ϸ0%; the sensitivity
of fluid culture for mycobacteria is Ϸ50%.20 Only patients at
high risk for tuberculous peritonitis, e.g., recent immigration
from an endemic area or acquired immunodeficiency syn-
drome, should have testing for mycobacteria on the first
ascitic fluid specimen.21
Multiple prospective trials show that bacterial growth
occurs in only about 50% of instances when ascitic fluid with
a polymorphonuclear (PMN) count H 250 cells/mm3 (0.25 ϫ
109/L) is cultured by ‘‘conventional’’ methods as compared
with approximately 80% if the fluid is inoculated into blood
culture bottles at the bedside.22-24
HEPATOLOGY Vol. 27, No. 1, 1998 RUNYON 265

3. Recommendations
1. The initial ascitic fluid analysis should include a cell
count and differential and serum-ascites albumin gradient.
(Rating, II B.)
2. When culture is performed, ascitic fluid should be
cultured at the bedside in blood culture bottles. (Rating, II B.)
Differential Diagnosis
Although cirrhosis is the cause of ascites formation in most
patients, approximately 20% of patients with ascites have a
cause other than liver disease. Approximately 5% of patients
with ascites have two or more causes of ascites formation, i.e.,
‘‘mixed’’ ascites.15,25 Usually these patients have cirrhosis plus
one other cause, e.g., peritoneal carcinomatosis or peritoneal
tuberculosis. Many patients with enigmatic ascites are eventu-
ally reported to have 2 or even 3 causes for ascites formation,
such as heart failure and diabetic nephropathy. In this setting
the sum of predisposing factors leads to sodium and water
retention when each individual factor might not be severe
enough to cause fluid overload.
TREATMENT OF ASCITES
Treatment
Appropriate treatment of patients with ascites depends on
the cause of fluid retention. The serum-ascites albumin
gradient can be helpful diagnostically, as well as in therapeu-
tic in decision making. Patients with low serum-ascites
albumin gradient ascites usually do not have portal hyperten-
sion and do not respond to salt restriction and diuretics,8
except when patients have nephrotic syndrome. In contrast,
patients with a high serum-ascites albumin gradient have
portal hypertension and usually are responsive to these
measures.7
The remainder of these guidelines applies only to patients
in which ascites is caused by cirrhosis.
Alcohol with or without hepatitis C is the most common
cause of liver disease that leads to high albumin gradient
ascites.11,26 One of the most important steps in treating this
form of ascites is to treat the underlying liver disease by
convincing the patient to abstain from alcohol. In a period of
months, abstinence can result in the improvement of the
reversible component of alcoholic liver disease. In a prospec-
tive study, abstinence has been shown to normalize portal
pressure in some, but not in all, patients.27 Ascites may
resolve or become more responsive to medical therapy during
this time. Non-alcoholic liver diseases are less reversible, and
by the time ascites is present, these patients may be better
candidates for liver transplantation than for protracted medi-
cal therapy.
The mainstays of treatment of patients with cirrhosis and
ascites include the following: 1) education regarding dietary
sodium restriction (2,000 mg/day [88 mmol/day]); and 2)
oral diuretics.7,11 More stringent dietary sodium restriction
can speed weight loss. Fluid loss and weight changes are
directly related to sodium balance in patients with portal
hypertension-related ascites. It is sodium restriction, not fluid
restriction, that results in weight loss as fluid passively
follows sodium.28 The measurement of urinary sodium excre-
tion is a helpful parameter to follow in these patients.
Random urinary sodium concentrations are of value when
they are 0 mmol/L or Ͼ 100 mmol/L; however, random
urinary sodium concentrations are much less helpful when
they are intermediate, because of lack of uniformity of
sodium excretion during the day and lack of knowledge of
total urine volume, which may vary from 300 mL to Ͼ 3,000
mL. Urine samples collected for twenty-four hours to deter-
mine sodium excretion are much more informative than are
random specimens; however, full-day collections are clumsy.
Providing patients with verbal and written instructions, a
container, and a lab order slip to turn in with the completed
specimen will help to insure patient compliance. The comple-
tion of the 24-hour specimen collection can be assessed by
measuring the levels of urinary creatinine. Cirrhotic men
should excrete 15 to 20 mg of creatinine per kilogram body
weight per day, and women should excrete 10 to 15 mg/kg per
day. Lower excretions of creatinine are indicative of an
incomplete collection. Total non-urinary sodium excretion is
Ͻ 10 mmol/day in afebrile cirrhotics without diarrhea.29 One
of the goals of treatment is to increase the urinary excretion of
sodium so that it is Ͼ 78 mmol/day (88 mmol/day of intake Ϫ
10 mmol/day of non-urinary excretion). Only the 10% to 15%
of patients who have spontaneous natriuresis (Ͼ 78 mmol/
day) can be considered for dietary sodium restriction alone,
i.e., without diuretics; however, when given a choice, most
patients prefer to take diuretics and to have a more liberal
sodium intake rather than to abstain from diuretics and to
have a more severe sodium restriction.
Fluid restriction is not a necessity when treating most
patients with cirrhotic ascites. The chronic hyponatremia that
is usually seen in patients with cirrhotic ascites is seldom
morbid. Rapid attempts to correct hyponatremia in this
setting can lead to more complications than can the hypona-
tremia itself.
The rapid correction of asymptomatic hyponatremia in the
patients with cirrhosis is probably only appropriate in the
immediate pre-liver transplant setting. Severe hyponatremia,
e.g., serum sodium Ͻ 120 mmol/L, does warrant fluid
restriction in the cirrhotic ascites patient. Cirrhotic patients
do not usually have symptoms from hyponatremia until their
sodium levels fall below 110 mmol/L or unless the decline in
sodium is very rapid.
Although conventional recommendations suggest bed rest,
based on extrapolation from heart failure, this recommenda-
tion is impractical and is not supported by controlled trials.
An upright posture may aggravate the plasma renin elevation
found in cirrhotic patients with ascites; theoretically, this may
increase sodium avidity. This theoretical concern must be
translated into clinically relevant outcomes before bed rest
could be advocated.
The usual diuretic regimen consists of single morning
doses of oral spironolactone and furosemide, beginning with
100 mg of the former and 40 mg of the latter.11 Previously,
single-agent spironolactone was advocated, but hyperkalemia
and the long half-life of this drug have resulted in its use as a
single agent only in patients with minimal fluid overload.30,31
A randomized controlled trial has revealed a two-week
interval before the onset of action of single-agent spironolac-
tone.31 Single-agent furosemide has been shown in a random-
ized controlled trial to be less efficacious than spironolac-
tone.32 The good oral bioavailability of furosemide in the
patient with cirrhosis, together with the acute reductions in
glomerular filtration rate associated with intravenous furose-
mide, favor the use of the oral administration.33,34
266 RUNYON HEPATOLOGY January 1998

4. The dose of both oral diuretics can be increased simulta-
neously, maintaining the 100 mg:40 mg ratio, if weight loss
and natriuresis are inadequate on the lower doses. In general,
this ratio maintains normokalemia. Maximum doses are 400
mg/day of spironolactone and 160 mg/day of furosemide.11
Furosemide can be temporarily withheld in patients present-
ing with hypokalemia. Patients with parenchymal renal
disease, e.g., diabetic nephropathy or immunoglobulin A
nephropathy, may tolerate less spironolactone than usual
because of hyperkalemia. Single morning dosing maximizes
compliance. Amiloride can be substituted for spironolactone,
but it is more expensive and has been shown to be less
effective in a randomized controlled trial.35
New loop diuretics must be proven to be superior to
current drugs before their expense can be justified.
This approach, dietary sodium restriction and dual diuretic
regimen, has been shown to be effective in 90% of patients in
the largest, multicenter, randomized controlled trial per-
formed in patients with ascites.36
Outpatient treatment can be initially attempted; however,
many patients with cirrhosis and ascites also have gut
hemorrhage, hepatic encephalopathy, bacterial infection,
and/or hepatocellular carcinoma, and, therefore, may require
hospitalization for definitive diagnosis and management of
their liver disease, as well as for management of their fluid
overload. Frequently, intensive education is required to
convince the patient that the diet and diuretics are actually
effective and worth the effort.
There is no limit to the daily weight loss of patients who
have massive edema. Once the edema has resolved, 0.5 kg is
probably a reasonable daily maximum.37 Encephalopathy,
serum sodium Ͻ 120 mmol/L despite fluid restriction, or
serum creatinine Ͼ 2.0 mg/dL should result in the cessation
of diuretics, the reassessment of the situation, and the
consideration of second-line options (see Refractory Ascites
later in paper).
In the past, patients with ascites frequently occupied
hospital beds for prolonged periods of time because of
confusion regarding diagnosis and treatment and also be-
cause of iatrogenic problems. Although an abdomen without
clinically detectable fluid is a reasonable ultimate goal, it
should not be a prerequisite for discharge from the hospital.
Patients who are stable, with ascites as their major problem,
can be discharged to the clinic after it has been determined
that they are responding to their medical regimen. However,
for patients to be discharged early from the hospital, they
should be observed in the outpatient setting promptly, ideally
within approximately one week of discharge.
Large volume paracentesis rapidly relieves tense ascites. A
study performed more than two decades ago showed that
paracentesis in this setting is hemodynamically beneficial to
the patient.38 A more recent study shows that a single 4 to 6 L
of paracentesis can be performed safely without post-
paracentesis colloid infusion in the patient with diuretic-
resistant tense ascites.39,40 However, large volume paracente-
sis does nothing to correct the underlying cause of ascites
formation, i.e., sodium retention. Large volume paracentesis
predictably removes the fluid more rapidly, in minutes, than
does careful diuresis, which may take from days to week.41
However, to prevent reaccumulation of fluid, sodium intake
should be reduced and urinary sodium excretion should be
increased with diuretics. The determination of optimal di-
uretic doses for each patient takes time as it involves the
process of titrating the doses upward until natriuresis and
weight loss are achieved. Although a controlled trial shows
that large volume paracentesis is faster than diuretic therapy
for patients with cirrhosis and tense ascites, it should not be
viewed as first line therapy for all patients with ascites.41
In the outpatient clinic, body weight, orthostatic symp-
toms, serum electrolytes, urea, and creatinine are monitored.
Random urine sodium concentration is measured if the
weight loss is inadequate. If urinary sodium concentration is
intermediate or if refractory ascites or non-compliance with
diet are suspected, 24-hour urine specimens can be collected
to assist with management decisions. Patients who are
excreting Ͼ 78 mmol/day and who are not losing weight
should be further counselled about restricting sodium in their
diets. These patients should not be labelled as diuretic-
resistant and should not proceed to second line therapy (see
later) until it is documented that they are compliant with the
sodium-restricted diet.
Patients who are excreting more than 78 mmol/day of
sodium in the urine with stable or increasing weight are
consuming more sodium in the diet than 88 mmol. Patients
who do not lose weight and who excrete Ͻ 78 mmol/day
should receive an attempt at a higher dose of diuretics.
Frequency of follow-up is determined by response to treat-
ment and by patient stability. Some patients warrant evalua-
tion every two to four weeks until it is clear that they are
responding to treatment and not developing problems; in
these patients, further evaluation every few months may be
appropriate. Intensive outpatient treatment, in particular diet
education, may help prevent subsequent hospitalizations.
The development of ascites as a complication of cirrhosis is
associated with a poor prognosis, with approximately a 50%
2-year survival.6 Liver transplantation should be considered
in the treatment options for these patients, especially when
local waiting times exceed 12 months.
Recommendations
1. Patients who drink alcohol and develop ascites should
be encouraged to abstain from alcohol consumption. (Rating,
III ACDE.)
2. A sodium restricted (88 mmol/day ϭ 2,000 mg/day)
diet, together with oral spironolactone and furosemide, is
effective in controlling fluid overload in 90% of patients with
cirrhosis and ascites and is also the mainstay of treatment.
(Rating, I CD.)
3. Fluid restriction is not necessary unless serum sodium
is Ͻ 120 mmol/L. (Rating, III D.)
4. Bedrest is not recommended. (Rating, III C.)
5. A single 4-to-6 L abdominal paracentesis should be
performed in patients with tense ascites. Sodium restricted
diet and oral diuretics should then be administered. (Rating, I
CD.)
6. Urine sodium excretion can assist in determining pa-
tient compliance with diet and diuretic-resistance. (Rating,
III DE.)
7. Diuretic-sensitive patients should preferably be treated
with sodium-restricted diet and oral diuretics rather than
with serial paracenteses. (Rating, III CD.)
8. Liver transplantation should be considered in eligible
patients with cirrhosis and ascites. (Rating, III ACD.)
HEPATOLOGY Vol. 27, No. 1, 1998 RUNYON 267

5. REFRACTORY ASCITES
Background
Refractory ascites is defined as fluid overload that is
nonresponsive to sodium-restricted diet and high-dose (400
mg/d of spironolactone and 160 mg/d furosemide) diuretic
treatment, in the absence of prostaglandin inhibitors, such as
non-steroidal anti-inflammatory drugs.42 Failure of diuretic
therapy may be manifested by the following: 1) minimal to no
weight loss, together with inadequate (Ͻ 78 mmol/d) urinary
sodium excretion, despite diuretics; or 2) development of
clinically significant complications of diuretics. Several ran-
domized trials have shown that Ͻ 10% of patients with
cirrhotic ascites are refractory to standard medical therapy.32,36
Options for patients refractory to routine medical therapy
include the following: 1) serial therapeutic paracenteses; 2)
liver transplantation; 3) peritoneovenous shunt; and 4)
transjugular intrahepatic portasystemic stent-shun.11,36,43,44
Serial therapeutic paracenteses are effective in controlling
ascites, a fact which has been known since the time of the
ancient Greeks. However, only recently have controlled trials
demonstrating the safety of this approach been pub-
lished.41,45,46 Even in patients without urine sodium excre-
tion, ascites can be controlled by paracenteses performed
approximately every 2 weeks. The frequency of paracentesis
provides insight into a patient’s degree of compliance with the
diet. The sodium concentration of ascitic fluid is approxi-
mately equivalent to that of plasma, which is 130 mmol/L in
these patients. A 6-liter paracentesis removes 780 mmol of
sodium (130 mmol/L ϫ 6 L ϭ 780 mmol). A ten-liter
paracentesis removes 1,300 mmol. Patients who consume 88
mmol of sodium per day, excreting Ϸ10 mmol/day in
non-urinary losses and excreting no urinary sodium, retain a
net of 78 mmol/day; therefore a 6-liter paracentesis removes
10 days (780 mmol:78 mmol/day) of retained sodium and a
ten-liter paracentesis removes Ϸ17 days of retained sodium
(1,300 mmol:78 mmol/day ϭ 16.7 days) in patients without
urinary sodium excretion. Patients with urinary sodium
excretion greater than zero should require paracenteses even
less frequently. Patients requiring paracenteses of Ϸ10 liters
more frequently than every 2 weeks are clearly not complying
with the diet.
In recent years, new paracentesis equipment has become
available that may improve the ease and speed of paracente-
sis. One controversial issue regarding therapeutic paracente-
sis is that of colloid replacement. In one study patients with
tense ascites were randomized to receive albumin (10 g per
liter of fluid removed) versus no albumin, after therapeutic
paracentesis.47 Refractoriness to diuretic treatment was not a
prerequisite for entry into this study; in fact, 31.4% of
patients had not received diuretics.47 The group that received
no albumin developed statistically significantly more changes,
although asymptomatic, in electrolytes, plasma renin, and
serum creatinine than did the albumin group, but no more
clinical morbidity or mortality.47 Although another study has
documented that the subset of patients who develop a
post-paracentesis rise in plasma renin have decreased life
expectancy, there has been no study large enough to show
decreased survival in patients who did not receive any plasma
expander compared with patients administered albumin after
paracentesis.48
Despite the lack of a proven survival advantage, albumin is
being used after therapeutic paracentesis. However, albumin
infusions markedly increase albumin degradation, and albu-
min is very expensive.49,50 In a study performed more than 30
years ago, 58% of infused albumin was accounted for by
increased degradation, and a 15% increase in serum albumin
led to a 39% increase in degradation.49 Increasing albumin
concentration in cell culture media has recently been shown
to decrease albumin synthesis.51 In view of the cost, i.e., $4 to
$25 per gram ϫ Ϸ50 g/tap ϭ $200 to $1,250/tap, it is difficult
to justify the expense of routine albumin infusion based on
the data at hand.
Non-albumin plasma expanders, such as dextran-70, he-
maccel, and even saline, have been advocated but without
demonstration of a survival advantage.52-54 Part of the contro-
versy regarding post-paracentesis plasma expanders relates to
study design. More studies are needed, in particular, studies
that target survival as the specific study endpoint in patients
with truly diuretic-resistant ascites. A single paracentesis
followed by diet and diuretic therapy is appropriate for tense
ascites.38,41 In the diuretic-sensitive patient, to serially remove
fluid by paracentesis, when it can be removed with diuretics,
seems inappropriate. Probably, only patients with diuretic-
resistant ascites should be treated with repeated large-volume
paracenteses. In addition, patients with early cirrhosis seem
to be more sensitive to volume changes than do patients with
advanced cirrhosis55; this may also help to explain the
changes in plasma renin when patients with early cirrhosis
receive large-volume paracenteses.47 Patients with early cirrho-
sis and diuretic-sensitive ascites should be treated with
diuretics and not with paracentesis; these patients may be
more sensitive to paracentesis-related volume depletion.55
Chronic therapeutic paracenteses should be reserved for the
10% of patients who truly fail diuretic treatment; these
patients may be less sensitive to paracentesis-related volume
depletion.
In addition, the most recent studies advocate giving 50% of
the plasma expander immediately after the tap and the other
half after 6 hours.48,52 This approach converts a brief outpa-
tient procedure into an all-day clinic visit or an overnight
hospitalization, which seems unwarranted. More convincing
data involving appropriate groups of patients and regarding
clinically relevant issues, rather than asymptomatic labora-
tory abnormalities, are required before albumin or other
plasma expanders can be recommended.
Liver transplantation should be considered in the treat-
ment options of patients with ascites. In some areas, patients
wait 12 to 18 months for liver transplants; deaths are
becoming increasingly common in patients awaiting transplan-
tation. In this setting transplant must be considered very
early after decompensationn first becomes evident. The
24-month survival of patients with cirrhosis and ascites is
50%.6 Once patients become refractory to routine medical
therapy, 50% die within 6 months.56 The 12-month survival
of patients with ascites refractory to medical therapy is only
25%.56
Peritoneovenous shunt, e.g., LeVeen or Denver, was popu-
larized in the 1970s as a physiologic treatment of ascites.
Shunt placement has been shown in controlled trials to
decrease the duration of hospitalization, to decrease the
number of hospitalizations, and to decrease the dose of
diuretics36,57; however, poor long-term patency, excessive
complications, and no survival advantage compared with
medical therapy in controlled trials have led to near abandon-
ment of this procedure.36,57 Shunt-related fibrous adhesions,
268 RUNYON HEPATOLOGY January 1998

6. and even ‘‘cocoon’’ formation, can make subsequent liver
transplantation difficult.58 Peritoneovenous shunting should
probably now be reserved for diuretic-resistant patients who
are not transplant candidates and who are not candidates for
serial therapeutic paracenteses because of multiple abdomi-
nal surgical scars or distance from a physician who is willing
and capable of performing paracenteses. Recent experience in
shunt insertion by the surgeon may also be a factor in
optimizing results in the rare patient who is selected to
undergo this procedure.
Transjugular intrahepatic portasystemic stent-shunt is a
side-to-side portacaval shunt that is placed by an interven-
tional radiologist, usually under local anesthesia.43,44 A ran-
domized trial has reported higher mortality in the transjugu-
lar intrahepatic portasystemic stent-shunt group compared
with the medically treated group.59 More randomized trials
are in progress, and their results are needed before the
position of transjugular intrahepatic portasystemic stent-
shunt in the treatment algorithm of patients with ascites can
be finalized. A recent National Institutes of Health Consensus
Conference has listed transjugular intrahepatic portasystemic
stent-shunt as ‘‘unproven’’ for treatment of refractory ascites
or hepatic hydrothorax.44
Recommendations
Treatment options for the 10% of patients with cirrhosis
and ascites who are truly diuretic-resistant include the
following:
1. Serial therapeutic paracenteses should be performed as
needed, approximately every two weeks. Post-paracentesis
albumin infusion is expensive and unproven to decrease
morbidity or mortality; it appears to be unnecessary for
paracenteses of Ͻ 5 L. For larger volume paracenteses, an
albumin infusion of I 50 g can be considered. (Rating, I CE.)
2. Liver transplantation should be considered if the patient
is an acceptable candidate. (Rating, III CD.)
3. Peritoneovenous shunt might be an option for patients
who are not transplant candidates. (Rating, I CD.)
SPONTANEOUS BACTERIAL PERITONITIS
Background
Diagnosis. This diagnosis is made when there is a positive
ascitic fluid bacterial culture, which is an elevated ascitic
fluid absolute polymorphonuclear leukocyte count, i.e., H
250 cells/mm3 (0.25 ϫ 109/L) without an evident intra-
abdominal and surgically treatable source of infection.12 An
abdominal paracentesis must be performed and ascitic fluid
must be analyzed before a confident diagnosis of ascitic fluid
infection can be made. A ‘‘clinical diagnosis’’ of infected
ascitic fluid without a paracentesis is inadequate.
Empiric Treatment. Patients with ascitic fluid polymorpho-
nuclear leukocyte counts H 250 cells/mm3 (0.25 ϫ 109/L), in
a clinical setting that is compatible with ascitic fluid infec-
tion, should receive empiric antibiotic therapy.12 An elevated
ascitic fluid polymorphonuclear leukocyte count probably
represents evidence of failure of the first line of defense, the
peritoneal macrophages, to kill invading bacteria.60 A prospec-
tive study in which two paracenteses were performed in rapid
sequence (Ϸ4 hours apart), before the initiation of antibiotic
therapy, shows that only 8% of patients with culture-positive
ascitic fluid with an elevated PMN count become culture-
negative spontaneously.61 The majority of patients with
culture-positive neutrocytic ascites show rising bacterial and
PMN counts when serial samples are obtained in rapid
sequence before initiation of antibiotic therapy.61
The ascitic fluid PMN count is more rapidly available than
is the culture and seems to be accurate in determining who
really needs empiric antibiotic coverage.12 Delaying treatment
until the ascitic fluid culture grows bacteria may result in the
death of the patient from overwhelming infection. In some
patients, infection is detected at the bacterascites stage before
there is a neutrophil response.62 Most patients with bacteras-
cites who do not resolve the colonization and who progress to
SBP have signs or symptoms of infection at the time of the
tap, which documents bacterascites.61,62 Therefore, patients
with cirrhotic ascites who have convincing signs or symp-
toms of infection should receive treatment, regardless of the
PMN count in ascitic fluid.
The patient with alcoholic hepatitis represents a special
case. These patients regularly develop fever, leukocytosis, and
abdominal pain which can masquerade as spontaneous
bacterial peritonitis (SBP). In addition, they can develop SBP.
These patients do not develop false-positive elevated ascitic
fluid PMN counts because of peripheral leukocytosis63; it
must be presumed that an elevated PMN count represents
SBP. Empiric antibiotic treatment, for presumed ascitic fluid
infection, of patients with alcoholic hepatitis who have fever
and/or peripheral leukocytosis can be discontinued after 48
hours if ascitic fluid, blood cultures, and urine cultures show
no bacterial growth.
A relatively broad-spectrum therapy is warranted in pa-
tients with suspected ascitic fluid infection until the results of
susceptibility testing are available. Cefotaxime, a third-
generation cephalosporin, has been shown to be superior to
ampicillin in combination with tobramycin in a controlled
trial.64 Cefotaxime or a similar third-generation cephalospo-
rin appears to be the treatment of choice for suspected SBP, as
it covers 95% of the flora, including the three most common
isolates, which are Escherichia coli, Klebsiella pneumoniae,
and the pneumococcus.12,64 IV dosing of 2 g cefotaxim every 8
hours results in excellent ascitic fluid levels, 20-fold killing
power after one dose.65 After sensitivities are known, the
spectrum of coverage can usually be narrowed. In a random-
ized controlled trial involving 100 patients, it has been
reported that 5 days of treatment is as efficacious as 10 days in
the treatment of carefully characterized patients with SBP.66
Distinction From Secondary Bacterial Peritonitis. Secondary
bacterial peritonitis, i.e., ascitic fluid infection caused by a
surgically-treatable intra-abdominal source, can masquerade
as SBP. Secondary peritonitis can be divided into two subsets:
those with free perforation of a viscus, e.g., duodenal ulcer,
and those with loculated abscesses in the absence of perfora-
tion, e.g., perinephric abscess. Signs and symptoms do not aid
in the separation of patients who need surgical intervention
(both subsets of secondary peritonitis) from those who have
SBP and who need only antibiotic treatment.67 In contrast,
the initial ascitic fluid analysis and the response to treatment
can assist with this important distinction.67 The characteristic
analysis in the setting of free perforation is PMN count H
250/cu mm (usually many thousands), multiple organisms
on gram stain and culture, and two or three of the following
criteria: total protein Ͼ 1 g/dL, lactate dehydrogenase greater
than the upper limit of normal for serum, and glucose Ͻ 50
mg/dL.67 It has been reported that these criteria have 100%
sensitivity but only 45% specificity in detecting perforation in
HEPATOLOGY Vol. 27, No. 1, 1998 RUNYON 269

7. a prospective study.67 Patients who fulfill these criteria should
undergo emergent plain and upright films, water-soluble
contrast studies of the gut, and computed tomographic
scanning.67 These criteria are only 50% sensitive in detecting
non-perforation peritonitis; the follow-up PMN count after
48 hours of treatment assists in detecting these patients.67
The 48-hour PMN count is essentially always below the
pretreatment value in SBP when an appropriate antibiotic is
used; in contrast, in non-perforation peritonitis the PMN
count rises despite treatment.67 Patients reported to have free
perforation or non-perforation peritonitis should receive
anaerobic coverage in addition to a third-generation cephalo-
sporin and laparotomy.67
Follow-Up Paracentesis. A follow-up ascitic fluid analysis is
not needed in all infected ascites patients. The majority of
patients have SBP in the typical setting, e.g., advanced
cirrhosis, with typical symptoms, typical ascitic fluid analysis
(total protein I 1 g/dL, lactate dehydrogenase less than the
upper limit of normal for serum, and glucose H 50 mg/dL), a
typical single organism, and a typical dramatic clinical
response.12 Repeat paracentesis can be performed to docu-
ment a culture’s sterility and dramatic decrease in PMN count
in patients with SBP; however, it is not necessary. In contrast
if the setting, symptoms, analysis, organism(s), or response
are atypical, repeat paracentesis can be helpful in raising
suspicion of secondary peritonitis and prompting further
evaluation and surgical intervention when appropriate.67
Possible Oral Treatment. Oral ofloxacin has been reported in
a randomized controlled trial to be as effective as parenteral
cefotaxime in the treatment of SBP in patients who are not
vomiting and not in shock.68 Confirmatory trials are awaited
before oral treatment of this life-threatening infection can be
enthusiastically recommended.
Recommendations
1. Patients admitted to the hospital with ascites should
undergo abdominal paracentesis. Paracentesis should be
repeated in patients, whether in the hospital or not, who
develop signs or symptoms or laboratory abnormalities
suggestive of infection (e.g., abdominal pain or tenderness,
fever, encephalopathy, renal failure, acidosis, or peripheral
leukocytosis). (Rating, III B.)
2. Patients with ascitic fluid PMN counts H 250 cells/mm3
(0.25 ϫ 109/L) should receive empiric antibiotic therapy, e.g.,
2 g of cefotaxime iv every 8 hours. (Rating, II BD.)
3. Patients with ascitic fluid PMN counts Ͻ 250 cells/mm3
(0.25 ϫ 109/L) and signs or symptoms of infection (tempera-
ture Ͼ100oF, abdominal pain or tenderness) should also
receive empiric antibiotic therapy, e.g., 2 g of cefotaxime iv
every 8 hours, while awaiting results of cultures. (Rating, II
BD.)
Prevention
The identification of risk factors for development of SBP,
including ascitic fluid protein concentration Ͻ1.0 g/dL,
variceal hemorrhage, and prior episode of SBP, has led to
randomized controlled trials of prophylactic antibiotics.69-72
The oral administration of 400 mg/d of norfloxacin has been
reported to successfully prevent SBP in the following: 1) in
patients with low-protein ascites; and 2) patients with prior
SBP.70,71 The oral adminstration of 400 mg/d of norfloxacin
twice per day for seven days helps to prevent infection in
patients with variceal hemorrhage72; however, oral antibiotics
do not prolong survival and do select resistant gut flora,
which can subsequently cause spontaneous infection.71-73 In a
report of liver transplant infections, one risk factor for fungal
infection was described as ’’prolonged therapy with ciprofloxa-
cin.’’74 Intermittent dosing, such as the following: 1) a single
weekly dose of 750 mg of ciprofloxacin; 2) five doses of
trimethoprim/sulfamethoxazole per week; or 3) restricting
use of norfloxacin to inpatients only, with discontinuation of
the drug at the time of discharge, may be the best compro-
mises in preventing infection without selecting resistant flora,
according to three randomized trials.75-77 However, studies
reporting substantial cost savings and/or survival advantages
for treated patients will be required before prophylaxis can be
enthusiastically recommended.
There are no published randomized trials of antibiotic
versus placebo in preventing infections in patients awaiting
liver transplantation.
To prevent sclerotherapy-related infections, parenteral anti-
biotics do not seem to be warranted, based on a controlled
trial78; rather, active bleeding seems to be the risk factor for
infection, not sclerotherapy. Variceal banding may replace
sclerotherapy. Antibiotics would be even less likely to be of
benefit in the setting of banding.
Recommendations
1. Short-term inpatient quinolone should be considered in
the prevention of bacterial infections in patients with the
following: 1) low-protein (Ͻ 1 g/dL) ascites; 2) variceal
hemorrhage; and 3) prior SBP. (Rating, I CD.)
2. Long-term outpatient use probably can be reserved for
patients who have survived an SBP episode. (Rating, I CD.)
APPENDIX
These guidelines were developed under the auspices of,
and approved by, the Practice Guidelines Committee of the
American Association for the Study of Liver Diseases. They
are intended to suggest preferable approaches to the clinical
management of liver diseases. They are flexible and are not
intended as the only acceptable approach to treatment. As the
appropriate level of skill or course of treatment will vary in
light of the relevant facts and circumstances surrounding
each individual case, these guidelines are not intended to
define the applicable standard of medical care and may be
updated periodically as new information becomes available.
Practice Guidelines Committee Members: Brian McMahon,
M.D., Chair, Department of Medicine, Alaska Native Medical
Center, Anchorage, AK; Leonard Seeff, M.D., VA Hospital,
Washington, DC; Roy Ferguson, M.D., Maurice and Sadie
Friedman Center, The Mt. Sinai Medical Center, Cleveland,
OH; Norman Grace, M.D., Division of Gastroenterology,
Faulkner Hospital, Boston, MA; William Carey, M.D., Cleve-
land Clinic, Cleveland, OH; Henrt Bodenheimer Jr, M.D., Mt.
Sinai Medical Center, New York, NY.
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