A Randomized Comparison of Rifaximin Versus Lactulose in Hospitalized Cirrhotic Patients With Renal Failure

Hepatic Encephalopathy (HE) is a reversible neuropsychiatric syndrome that develops in
patients with cirrhosis due to the accumulation of a variety of toxic substances that are
produced from bacteria in the gastrointestinal tract. It is characterized by slowing of
function of the brain function and ranges in severity from mild cognitive impairment (grade
1), presence of a shaking tremor called asterixis (grade 2), lethargy but arousable state
(grade 3), and coma (grade 4). Decreased kidney function exacerbates the condition, and
hospitalized patients with cirrhosis with new onset kidney failure are at risk for the
development of severe HE.

Possible treatments for HE include lactulose and antibiotics. Lactulose reduces the
production of many of the toxins by the bacteria, and antibiotics work by reducing the
number of bacteria in the gastrointestinal tract. Rifaximin is an antibiotic that is an
antibiotic that is not absorbed, possesses a wide antibacterial spectrum, and was approved
by the Food and Drug Administration in 3/2010 for prevention of relapse for patients with
recurrent severe hepatic encephalopathy. The aim of the current study is to determine
whether rifaximin or lactulose is more effective in preventing the development of severe
hepatic encephalopathy in hospitalized patients with cirrhosis and new onset kidney failure.

To determine whether rifaximin or lactulose is more effective in preventing severe HE,
seventy consecutive hospitalized patients with cirrhosis and new onset kidney failure will
be recruited. New onset kidney failure will defined as a progressive and sustained increase
in serum creatinine >0.5mg/dl from baseline to a value of 2.0mg/dl or greater within 3 days.
Subjects will be randomly assigned to one of two treatment groups:

Group A: Lactulose 20g dose titrated to 2-3 soft-formed bowel movements per day Group B:
Rifaximin 550mg tablet twice daily. Subjects will be followed daily for two weeks or until
hospital discharge. Severity of hepatic encephalopathy will be graded by physical
examination, review of hospital chart, and performance of standard paper and pencil tests
that evaluates the ability to concentrate. In addition, approximately one tablespoon will be
drawn twice a week at every 3 to 4 day for ammonia level and other toxins. A sample of
breath will also be collected by having the subjects breathe into a collection bag to
measure substances that determine whether there are bacteria present in the small intestine.
Treatment success is defined as prevention of grade 3 or 4 HE during hospitalization.

Inclusion Criteria:

1. Age 18 years or older

2. Cirrhosis of the liver based on biopsy or clinical and radiographic criteria

3. Ability to provide informed consent (Grade 0 to 1 HE)

4. Acute renal failure (increase in baseline creatinine of 0.5mg/dL to a value of >2.0
mg/dL within 3 days).

5. Absence of improvement in renal function after adequate fluid resuscitation using
either normal saline or blood products (25% salt poor albumin, fresh frozen plasma,
or packed red blood cells)

Exclusion Criteria:

1. Previous history of sensitivity/allergy to lactulose or rifaximin or rifampin

2. Pregnancy

3. Inability to obtain informed consent