Treatment Options for Hepatic Encephalopathy

Thomas D. Schiano, M.D.

Few formal treatment guidelines exist for managing hepatic encephalopathy.
The nonabsorbable disaccharide, lactulose, is considered the first-line
therapeutic agent for treating hepatic encephalopathy. Acidification of the
gastrointestinal tract is the principal mechanism by which the drug inhibits
production of ammonia by coliform bacteria. Elevated ammonia levels are
seen in more than 80% of patients with hepatic encephalopathy. Systemic
antibiotics, primarily neomycin, have also been employed to reduce bacterial
production of ammonia, but associated adverse events limit their use in
patients with hepatic encephalopathy. The semisynthetic, nonsystemic
antibiotic, rifaximin, was approved in March 2010 by the United States Food
and Drug Administration for the treatment of overt hepatic encephalopathy.
Rifaximin decreases intestinal production and absorption of ammonia by
altering gastrointestinal flora and is almost completely excreted unchanged in
the feces. Rifaximin has been effective in improving behavioral, laboratory,
mental, and intellectual abnormalities in patients with hepatic encephalopathy. The drug was compared with lactulose in well-designed clinical
studies in patients with hepatic encephalopathy. Rifaximin was generally
found to be equal or superior to lactulose in these studies. Although dosages
have varied, most medical centers use a dosage of rifaximin 400 mg 3
times/day for hepatic encephalopathy. Recent clinical trials have used 550 mg
twice/day in order to improve patient compliance. Additional clinical trials
are being undertaken to further define the efficacy and safety of rifaximin in
hepatic encephalopathy.
Key Words: ammonia, Clostridium difficile, cirrhosis, hepatic encephalopathy,
lactulose, neomycin, nonabsorbable disaccharides, portosystemic encephalopathy, rifaximin.
(Pharmacotherapy 2010;30(5 Pt 2):16S21S)
Initial treatment protocols, going as far back as
the 1970s, lacked a formal definition of hepatic
encephalopathy, grading scales for the disease,
and results from placebo-controlled clinical
studies. These deficiencies have limited the
From the Division of Liver Diseases, Mount Sinai Medical
Center, New York, New York.
Based on a presentation at the Special Issues Related to
Pharmacists in the Management of Hepatic Encephalopathy
Advisory Board Meeting held in Las Vegas, Nevada,
December 5, 2009, and supported by an unrestricted
educational grant from Salix Pharmaceuticals, Inc.,
Morrisville, North Carolina.
For reprints, visit http://www.atypon-link.com/PPI/loi/phco.
For questions or comments, contact Thomas D. Schiano,
M.D., Division of Liver Diseases, Mount Sinai Medical
Center, Box 1104, One Gustave Levy Place, New York, NY
10029; e-mail: thomas.schiano@mssm.edu.

formation of treatment guidelines, particularly

when measuring the effects of newer therapies.
Published studies over the last 10 years have
exploded in number, further underlying the need
for evidence-based reviews of treatment strategies
for hepatic encephalopathy. Such reviews,
however, would go far beyond the scope of this
brief overview of currently available treatment
options.
Therapy that reduces ammonia levels has
received a great amount of attention because
elevated levels are seen in more than 80% of
patients with hepatic encephalopathy. Although
removal of ammonia appears to be important in
the treatment of hepatic encephalopathy, the
relationship between ammonia levels and the

TREATMENT OPTIONS FOR HEPATIC ENCEPHALOPATHY Schiano

pathogenesis of the disease has yet to be
confirmed. On the other hand, an elevated
ammonia level above 250 mol/L in an individual
with fulminant hepatic failure is a key issue and
bodes for an extremely poor prognosis. However,
the disease pathophysiology in patients with
fulminant hepatic failure is different from that of
patients with hepatic encephalopathy.
Treatment for hepatic encephalopathy includes
ruling out nonhepatic causes of diminished
mental function; providing specialized nursing
care that includes frequent neurological checks;
treating precipitating factors, such as sepsis and
electrolyte disturbances; initiating therapy based
on the ammonia hypothesis; and managing
severe hepatic encephalopathy in the intensive
care unit (ICU), if possible. This article will
review several treatment modalities available for
hepatic encephalopathy, with particular emphasis
on rifaximin dosed twice/day.
Pharmacotherapy for Hepatic Encephalopathy
Lactulose
Nonabsorbable disaccharides are considered
the standard of care for hepatic encephalopathy.
These products include lactulose and lactitol
(lactitol is not available in the United States).
The evidence to support or refute the use of these
agents alone in the treatment of hepatic encephalopathy is insufficient.13 Lactulose, however, was
the only pharmacologic agent available in the
United States for the treatment of hepatic
encephalopathy for many years.3 The drug is
effective in patients with cirrhosis who have
minimal hepatic encephalopathy (MHE).49 An
analysis of Cochrane Hepato-Biliary Group data
demonstrated efficacy of lactulose over placebo,
but showed no benefit in survival.1 Lactulose has
been shown to improve cognitive function and
health-related quality of life in patients with
MHE. 7 However, it is difficult to objectively
assess improvement in quality of life in patients
with MHE. A recent study found that lack of
response to lactulose treatment in cirrhotic
patients with MHE was attributed to low serum
sodium levels and high venous ammonia levels.10
Lactulose is metabolized into lactic and acetic
acids, which results in acidification of the gastrointestinal lumen. Gastrointestinal acidification
ultimately inhibits the production of ammonia by
coliform bacteria. Lactulose also acts as a
cathartic. The typical dosage of lactulose is 30
ml 24 times/day, adjusted to achieve two to four
soft stools/day. 3 It is not easy to follow this

17S

regimen because of the necessary dosage adjustments, making compliance an issue. Inadequate
compliance is a recognized limitation of lactulose
therapy.3 For this reason, continuous counseling
of patients is important. Abdominal cramping,
diarrhea, and flatulence are common adverse
events with lactulose. 3 Diarrhea may lead to
other adverse events, including dehydration, 2
hypernatremia,2, 11 and hypokalemia.11 Nausea
and vomiting have also been reported.11 In short,
lactulose is not a benign drug.
Questions always seem to arise about lactulose
administration. Which is the preferred route
nasogastric tube or enema? At Mount Sinai
Medical Center, we prefer to use a nasogastric
tube; however, a patient must then be monitored.
In the ICU, monitoring is not an issue. However,
outside the ICU, if the need arises for administration of lactulose, for example, at midnight,
when the house officer is busy taking care of
several patients, it is much easier and quicker to
use an enema than a nasogastric tube. Still, an
enema must be placed high up in the intestine,
which suggests that acidification of the gastrointestinal lumen is more important than the
bowel-cleaning effect. Lactulose enemas may not
always be effective because it is difficult for the
patient to retain the enema contents. With
nasogastric tubes, patients may be predisposed to
aspirate because of the gaseous distention that
lactulose causes, especially in the setting of
appreciable ascites.
Neomycin
Given the primary role of gastrointestinal
tractderived ammonia in hepatic encephalopathy,
one therapeutic approach to management involves
the use of antibiotics directed at reducing bacterial
production of ammonia. The U.S. Food and Drug
Administration (FDA) has approved neomycin for
acute hepatic encephalopathy but not for chronic
hepatic encephalopathy. No controlled trials with
neomycin have demonstrated equal or superior
efficacy to lactulose. The recommended dosage
of neomycin for patients with acute hepatic
encephalopathy is 1 g every 6 hours; for patients
with chronic hepatic encephalopathy, the
recommended dosage is 12 g/day. Although
neomycin is poorly absorbed, chronic administration may result in nephrotoxicity and
ototoxicity.
Adverse events tend to limit the use of conventional antibiotics in the treatment of hepatic
encephalopathy. The potential for adverse events

18S

Supplement to PHARMACOTHERAPY Volume 30, Number 5, 2010

precludes the use of antibiotics, such as neomycin

and metronidazole, as first-line therapy. Not only
is there a risk of infection by the opportunistic
pathogen Clostridium difficile, but there is an
increased risk of serious adverse events with
prolonged therapy. 3 As patients are waiting
longer for liver transplants, and they are in the
hospital and thus at greater risk for developing
nosocomial infections, the long-term use of any
antibiotic has to be questioned.
Zinc
Zinc deficiency is common in patients with
cirrhosis; the metal has been shown to increase
urea formation from amino acids and ammonia.11
In hepatic encephalopathy, zinc appears to reduce
ammonia levels; however, the metal is rarely used
as a primary or secondary agent in the treatment
of hepatic encephalopathy.
Combination Therapy
A synergistic effect is achieved by combining
lactulose and nonabsorbable antibiotics; thus,
reduced doses of each drug can be administered.
Reduced doses of lactulose may improve
compliance. On the other hand, long-term use of
antibiotics, even when cycled, poses the danger
of bacterial overgrowth, bacterial resistance, and
fungal colonization.
Rifaximin
Rifaximin is a semisynthetic, nonsystemic
antibiotic that is almost exclusively and completely excreted in the feces as unchanged drug.
It was approved in late March 2010 by the FDA
for the treatment of overt hepatic encephalopathy.12
It is believed that by altering the flora in the
gastrointestinal tract, rifaximin decreases intestinal production and absorption of ammonia.
Rifaximin has a broad spectrum of antibacterial
activity and thus may be an appropriate agent for
eliminating both the anaerobic and aerobic
colonic bacteria that are capable of producing
ammonia.
Rifaximin is well tolerated in nearly all patient
populations, including young children. 13 No
dosage adjustment is needed in patients with
hepatic encephalopathy. 14 Rifaximin has not
been found to contribute to clinically relevant
bacterial resistance, which is often a problem
with antibiotic therapy.
One of the issues concerning the use of
rifaximin is its relatively high cost. It is hoped

that this cost, however, can be offset by shorter

hospital stays for patients with hepatic encephalopathy. A pilot study analyzing hospitalizations
among patients with end-stage liver disease
suffering from hepatic encephalopathy showed
that the average length of stay was 3.5 days in the
rifaximin-treated group and 5.0 days in the
lactulose-treated group.15
A review of placebo-controlled, comparative
treatment, and open-label studies of the use of
rifaximin in patients with hepatic encephalopathy was published in 2008.16 Rifaximin was
judged to be efficacious in improving the behavioral, laboratory, mental status, and intellectual
abnormalities seen in patients with hepatic
encephalopathy. Patients with hepatic encephalopathy who were administered rifaximin had
fewer hospitalizations, shorter durations of
hospitalization, and lower hospital charges
compared with lactulose-treated patients.
Rifaximin was found to be at least equally
effective as, and, in some studies, superior to,
nonabsorbable disaccharides in reducing signs
and symptoms in patients with mild-tomoderately severe hepatic encephalopathy.
Nine open-label studies and four double-blind
studies that compared rifaximin with either
nonabsorbable disaccharides or antibiotics in the
treatment of hepatic encephalopathy were
reviewed. 17 Although all these studies had
various limitations, they reported that rifaximin
displayed superior efficacy to lactulose and
similar or greater efficacy than neomycin. In
these studies, rifaximin therapy was associated
with fewer hospitalizations, fewer days of
hospitalization, and lower hospitalization costs
than lactulose.
Rifaximin was compared with neomycin in
patients with portosystemic encephalopathy and
was found to be at least as effective or better than
neomycin in reducing ammonia levels,
bradyarthria (abnormal slowness or deliberation
of speech), and flapping tremor, as well as in tests
to assess cognitive and behavioral deficits.1820
A double-blind clinical study evaluated the
effect of rifaximin, lactitol, and the combination
of the two drugs in the treatment of patients with
viral liver cirrhosis and chronic hepatic encephalopathy.21 All three treatments reduced signs and
symptoms of hepatic encephalopathy with
differing efficacy. Patients in the rifaximin and
rifaximin-lactitol groups achieved significantly
faster improvement in the degree of hepatic
encephalopathy (p<0.05); a higher percentage of
these patients returned to a normalized mental

TREATMENT OPTIONS FOR HEPATIC ENCEPHALOPATHY Schiano

state (based on the number connection test) and
had faster improvement of asterixis and longer
persistence of normal ammonia levels than
patients in the lactitol group. Rifaximin in
combination with lactitol represented a safe
and effective treatment of chronic hepatic
encephalopathy.
The initial dosing study with rifaximin,
conducted earlier in this decade, was conducted
in patients with cirrhosis and mild-to-moderate
hepatic encephalopathy.22 Patients were administered rifaximin 600, 1200, or 2400 mg/day in
three divided doses. The primary outcome
measure was change in portosystemic encephalopathy index, which was calculated from mental
state, asterixis, number connection test time,
electroencephalogram mean frequency, and blood
ammonia level. There was a trend toward a
greater treatment effect with the highest
rifaximin dose (2400 mg/day), but no dramatic
differences were noted between the 1200-mg/day
and 2400-mg/day doses, which is why most
medical centers use a dosage of 400 mg 3
times/day.
Emerging data concerning the efficacy of
rifaximin in reducing the risk of breakthrough
hepatic encephalopathy and hospitalizations in
patients in remission from previous episodes of
hepatic encephalopathy have been assessed. The
effects of rifaximin 550 mg twice/day were
evaluated a phase III, randomized, placebocontrolled, double-blind, multicenter, multinational trial conducted at 70 centers in the
United States, Canada, and Russia among 299
patients enrolled between December 2005 and
February 2008.2326 To be included in the study,
patients had to have two or more episodes of
hepatic encephalopathy associated with cirrhosis
or portal hypertension within 6 months of
screening. In addition, they had to be in hepatic
encephalopathy remission, with a model for endstage liver disease (MELD) score of 25 or lower.
Patients underwent an observation period and
were then randomized either to placebo (159
patients) or rifaximin 550 mg twice/day (140
patients). They were permitted to take lactulose
concomitantly with their study drugs. Treatment
was administered for 6 months, followed by an
open-label crossover phase. The two groups had
similar demographics. Seventeen percent of
patients in each group discontinued therapy, and
91% in each group used lactulose during the
treatment period.
The risk of a breakthrough episode of hepatic

19S

encephalopathy was reduced by 77% (108

patients) in the rifaximin group and by 53% (84
patients) in the placebo group23; the difference
between groups was significant (p<0.0001). This
significant difference in risk reduction in the
rifaximin group compared with that in the
placebo group was observed across all subgroups
(male vs female, age < 65 yrs vs age 65 yrs,
Caucasian vs non-Caucasian, patients with vs
without diabetes mellitus, MELD score 25 vs
MELD score > 25, Conn score).24 In addition,
the reduction in breakthrough episodes in the
rifaximin group was accompanied by a 50%
reduction in hospital readmissions. 25 This
reduction was substantial, giving further
credence to the proposition that the cost of
rifaximin could be offset, or at least be partially
offset, by a reduction in hospital costs. The
safety profile of rifaximin was comparable to that
of placebo in this study.26
Drugs and Devices That Eliminate Ammonia
from Plasma
Several drugs and one device may help in the
treatment of hepatic encephalopathy specifically
by eliminating ammonia from the blood. Sodium
benzoate and sodium phenylacetate both
enhance tissue metabolism of ammonia. Sodium
benzoate conjugates with glycine to form
phenylacetate glutamine. Sodium benzoate and
sodium phenylacetate bind with ammonia substrates and thus take them out of the circulation.
Both sodium benzoate and sodium phenylacetate
are readily excreted by the kidneys. The use of
these drugs has led to a reduction in morbidity
and mortality from inborn errors of the urea
cycle.27 One small study reported that sodium
benzoate was as effective as lactulose in reducing
ammonia levels and improving cognitive
function. 28 Unfortunately, severe accidental
overdose has been reported, presumably due to
the infrequent use of the drugs.27
The molecular adsorbant recirculating system
(MARS) is a detoxification system that combines
hemodialysis with adsorption using albumin.
The device removes protein-bound and watersoluble toxins. A short-term (5-day), multicenter,
randomized study compared the use of MARS
with standard medical therapy.29 Significantly
more rapid improvement in mental status was
observed in the MARS group (p=0.044). The role
of albumin dialysis, however, needs to be
evaluated in well-controlled studies.

20S

Supplement to PHARMACOTHERAPY Volume 30, Number 5, 2010

Probiotics
Probiotics are live, microbiologic dietary supplements (e.g., yogurt) that have beneficial effects
beyond their nutritive value. They may work by
depriving pathogenic bacteria of substrates and
providing fermentation products for beneficial
bacteria. Two small studies reported neuropsychological improvement in patients with MHE.30, 31
Further studies with probiotics are needed.
Conclusion
Lactulose remains the first-line agent for both
acute episodic and persistent hepatic encephalopathy. Rifaximin is the second-line agent, either
when used alone or in combination with lactulose.
Results of several clinical studies suggest that
rifaximin 400 mg 3 times/day or 550 mg twice/day
is suitable for the treatment of hepatic encephalopathy, is very well tolerated, and is at least as
effective as other commonly used agents such as
lactulose or neomycin. More data are needed to
assess the effects of rifaximin alone versus
rifaximin combined with lactulose, particularly
in patients with MHE. Additional well-controlled
clinical trials are being conducted to further
define the efficacy and safety of rifaximin for
hepatic encephalopathy.
Participants Discussion
After the live presentation that was the basis
for this article, pharmacists participated in a
panel discussion.
1. How do you deal with deafness associated
with neomycin?
Dr. Schiano responded that a hearing deficit is
very difficult for the patient to assess. It is the
patients family and friends who notice that the
patient is talking louder, that the television is
at a higher volume, and that the patient begins
to request that words or sentences be repeated.
For this reason, he recommends that audiometric
examinations be performed for patients who
have been taking neomycin for more than 68
months. Another participant pointed out that
it is often difficult to blame the hearing loss on
neomycin, since other drugs that the patient
may be taking may also cause nephrotoxicity.
Dr. Schiano admitted to a bias against the use
of neomycin and said that he prescribes it to
be added only after combination therapy with
lactulose and rifaximin is not sufficiently
effective.

2. What are your prescribing practices for

lactulose?
Dr. Schiano replied that a few years ago he
noticed that prescribing practices among
physicians at Mount Sinai Medical Center were
very nonuniform, despite each provider having
a conviction on knowing how to prescribe
lactulose. His facility has a computerized
order entry system that allows for insertion of
standardized text for each prescription. For
each lactulose prescription, he requests that
the standardized text be changed to adjust
not titratethe dosage of lactulose to
achieve 23 loose stools/day.
3. Do you ever use branched-chain amino acids?
Dr. Schiano replied that he had never seen
them used at his facility.
4. What is the position of metronidazole in the
therapeutic picture?
Dr. Schiano ranked the therapeutic approaches
from first to last as follows: lactulose,
rifaximin, neomycin, and metronidazole.
5. Do you use combination therapy for hepatic
encephalopathy empirically?
Dr. Schiano replied that add-on therapy is used
at his facility, unless unfavorable tolerability
argues that one agent should be stopped and
another begun. When a patients condition is
not controlled with lactulose, rifaximin is
added. A patient who does not tolerate
lactulose because of diarrhea or dehydration is
switched to rifaximin.
6. Is the emergence of C. difficile a problem in
the treatment of hepatic encephalopathy?
One participant pointed out that the occurrence
of C. difficile has increased significantly at his
institution among patients who underwent
liver transplantation. Patients had been
administered lactulose and rifaximin. It was
his belief that the increased occurrence of C.
difficile was probably caused by a more
resistant strain resulting from the use of
several drugs that produced a broad spectrum
of activity, including extended anaerobic
coverage. Nonetheless, he cautioned that the
possibility of linkage between the use of
rifaximin and the increased occurrence of C.
difficile should be kept in mind.
7. Why was a dosage of rifaximin 550 mg
twice/day used in the large-scale clinical study
since most medical centers have reported

TREATMENT OPTIONS FOR HEPATIC ENCEPHALOPATHY Schiano

dosages of 400 mg 3 times/day?
Dr. Schiano replied that only so much active
drug could be formulated into a tablet before it
became too large for the patient to swallow,
and the dose was specially formulated for this
study in order to provide a twice-daily dosing
schedule to improve compliance.
8. Have there been any dispensing errors related
to rifaximin at your facility (e.g., rifampin
dispensed in error)?
Dr. Schiano replied that none had ever occurred.
He pointed out that when drugs are arranged
alphabetically, and rifaximin is placed next to
rifampin, there is always the chance for a
dispensing error. He called for better labeling
to minimize the possibility.

13.
14.
15.

16.
17.
18.

19.
20.

Acknowledgment
The author acknowledges SOMA Medical Education
and Richard Bell Smith, medical writer, for their
assistance in preparing this manuscript for publication
from the authors original creation.

21.

22.

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