Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX

Transcription

1 ANTIBIOTICS FOR HEPATIC ENCEPHALOPATHY Role of Antibiotics in the Management of Hepatic Encephalopathy Willis C. Maddrey, MD Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX This article explores the rationale for use of antibiotics in the treatment of hepatic encephalopathy, discusses the role of antibiotics relative to other therapeutic approaches, and considers the reasons that limit the use of the antibiotics most commonly prescribed for the management of hepatic encephalopathy in the United States. Although the scientific rationale for the use of antibiotics in hepatic encephalopathy is well founded, the clinical evidence for their benefits is rather limited. There is no doubt that many antibiotics cause a decrease in intraluminal production of ammonia. However, the commonly prescribed antibiotics are also associated with a variety of adverse effects. None of the antibiotics typically used for hepatic encephalopathy is adequately tolerated in the target patient population. The clinical evidence to date does not support the first-line use of currently available antibiotics in the treatment of hepatic encephalopathy. To improve upon current antibiotic offerings for hepatic encephalopathy, an antibiotic should provide broad-spectrum coverage against both aerobic and anaerobic bacteria, effectively control neuropsychiatric signs and symptoms, and be extremely well tolerated in the target population. An antibiotic fulfilling these criteria would constitute an advance in therapy for hepatic encephalopathy. [Rev Gastroenterol Disord. 2005;5(suppl 1):S3-S9] 2005 MedReviews, LLC Key words: Ammonia Antibiotics Gut bacteria Hepatic encephalopathy Lactulose Neuropsychiatric signs An important and distressingly frequent complication of chronic liver disease, hepatic encephalopathy is a neuropsychiatric syndrome characterized by alterations in consciousness and cognition; neuromuscular abnormalities such as tremor, asterixis, and hyperreflexia; characteristic electroencephalographic (EEG) abnormalities; and, often, elevations in blood ammonia (Table 1). 1-4 Neurocognitive manifestations, often reversible, range from mild VOL. 5 SUPPL REVIEWS IN GASTROENTEROLOGICAL DISORDERS S3

2 Managing Hepatic Encephalopathy continued Table 1 Main Neuropsychiatric Signs and Symptoms of Hepatic Encephalopathy as a Function of Stage of Disease Personality EEG Stage Consciousness and Intellect Neurologic Signs Ammonia Level* Findings Subclinical Normal Normal Impaired Normal Normal psychomotor testing Stage 1 Insomnia, disturbed Confusion, Tremor, Slightly sleep pattern forgetfulness, constructional abnormal agitation apraxia, uncoordination Stage 2 Lethargy Disorientation, Asterixis, Slowing of bizarre behavior ataxia triphasic waves Stage 3 Somnolence, but Disorientation, Asterixis, hyperactive Slowing patient may be aggression reflexes, positive of triphasic arousable Babinski reflex waves Stage 4 Coma, Coma Decerebrate Slow waves unresponsiveness posture (2 to 3 cycles per second) *Levels range from slightly elevated ( ) to extremely elevated ( ). EEG, electroencephalogram. Adapted with permission from Abou-Assi S and Vlahcevic ZR. 1 Copyright 2001 The McGraw-Hill Companies. All rights reserved. alteration of consciousness to coma. 1,5 The manifestations of hepatic encephalopathy are hypothesized to arise from excessive blood and brain levels of ammonia and, probably, other toxins that are generated in the gut by intestinal bacteria and inadequately detoxified by the liver. Although several toxins have been hypothesized to be important in hepatic encephalopathy, ammonia remains the toxin of greatest interest. Reduction of the production and absorption of ammonia is one of the goals of treatment of hepatic encephalopathy. 4 Antibiotics potentially play an integral role in the management of hepatic encephalopathy because they can reduce or eliminate ammonia-producing bacteria and can decrease the rate of production of ammonia at its source. Despite the convincing theoretical foundation for the utility of antibiotics in hepatic encephalopathy, antibiotics are not widely used as first-line treatment of hepatic encephalopathy in the United States. This article explores the rationale for use of antibiotics in hepatic encephalopathy, discusses the role of antibiotics relative to other therapeutic approaches, and considers the reasons why currently available antibiotics are not as widely used as other approaches in the management of hepatic encephalopathy. Pathophysiology of Hepatic Encephalopathy: A Central Role of Gut Bacteria Much of the body s ammonia is produced in the small and large intestines. 6 Ammonia is produced in the colon as a by-product of the breakdown of proteins and urea by the bacterial flora. Ammonia is produced in the small intestine during the bacterial degradation of the amino acid glutamine, which is a primary source of energy for mucosal cells. 6 In chronic hepatic encephalopathy, the liver inadequately detoxifies ammonia because of hepatocellular failure arising from liver damage and/or because of portosystemic shunting induced by portal hypertension, in which toxins bypass the liver via a collateral venous circulation emptying directly into the systemic blood systems. 4 Because of the failure of the liver to remove ammonia from portal blood, systemic levels of ammonia become elevated, with a resultant increase in exposure of the brain and other tissues to ammonia. 1 In the brain, ammonia in excessive levels contributes to disruption of neurotransmission and causes neuropsychiatric abnormalities. Observations consistent with an integral role of ammonia in the pathogenesis of hepatic encephalopathy S4 VOL. 5 SUPPL REVIEWS IN GASTROENTEROLOGICAL DISORDERS

3 Managing Hepatic Encephalopathy include elevated blood ammonia levels in patients with cirrhosis; increased cerebral metabolism of ammonia, as suggested by positron emission tomography (PET) data in patients with hepatic encephalopathy; and enhanced permeability of the blood-brain barrier to ammonia in patients with hepatic encephalopathy. 1,7 Astrocytes, the only brain cell type that can metabolize ammonia, 8 are characteristically increased in patients with hepatic encephalopathy; neurons generally appear histologically normal. The accumulation in astrocytes of glutamine, a product of the detoxification of ammonia, is hypothesized to cause Alzheimer type II astrocytosis, which is manifested by swollen astrocytes with enlarged nuclei and the displacement of chromatin to the cellular periphery. 1,5 The glutamine accumulation that promotes Alzheimer type II astrocytosis may disrupt the normal osmotic gradient across the blood-brain barrier, leading to cerebral edema and other manifestations of osmolyte dysregulation. 3 The idea that ammonia contributes to causing Alzheimer type II astrocytosis is supported by the observation that cellular pathology characteristics of Alzheimer type II astrocytosis can be experimentally produced in vitro via application of ammonia to cell preparations. 4 Besides causing structural changes in brain tissue, ammonia causes functional changes that appear to underlie the neuropsychiatric abnormalities in hepatic encephalopathy. Ammonia can affect neurotransmission directly by blunting excitatory postsynaptic potentials to depress brain function and indirectly by altering brain uptake of substances that are involved in neurotransmission, such as amino acids. 1 General depression of brain function in patients with hepatic encephalopathy is revealed by the results of PET studies showing decreased utilization of glucose (corresponding to decreased energy expenditure) in the cerebral cortex and increased glucose utilization in the thalamus, caudate, and cerebellum. In addition to effecting global depression of brain function, ammonia causes neurotransmitter systemspecific functional changes that may contribute to neuropsychiatric abnormalities. For example, ammonia is hypothesized to facilitate the generation of false neurotransmitters such as octopamine and phenylethanolamine, which are synthesized from aromatic amino acids (eg, tyrosine, phenylalanine, and tryptophan). 3 The aromatic amino acids and the branchedchain amino acids (eg, valine, leucine, and isoleucine) compete for entrance into the brain via an amino acid carrier. Brain ammonia is thought to play an important role in facilitating transport of aromatic amino acids across the blood-brain barrier: the amino acid transporter moves an aromatic amino acid into the central nervous system in exchange for glutamine generated from the detoxification of ammonia in astrocytes. In hepatic encephalopathy, plasma amino acids are imbalanced such that branched-chain amino acids are deficient whereas aromatic amino acids are overabundant. 2 The ratio of branched-chain amino acids to aromatic amino acids in the bloodstream is 3.5:1 in healthy individuals compared with 1:1 in patients with cirrhosis. 1 The overabundance of aromatic amino acids in the plasma may result in their excess accumulation in the brain, where they act as false neurotransmitters that compete with true neurotransmitters for brain receptor sites. Because the false neurotransmitters are considerably less potent at the receptors than are true neurotransmitters, brain function is impaired. Besides false neurotransmitters, other neurotransmitter abnormalities most of which have been linked to the toxic influence of ammonia on brain function possibly explain the neuropsychiatric abnormalities observed in hepatic encephalopathy. Among the neurotransmitter abnormalities hypothesized to contribute to hepatic encephalopathy are elevations in -aminobutyric acid (GABA), which is the primary inhibitory neurotransmitter; elevations in monoaminergic activity; and dysfunctional opioid activity. 1,7,9,10 The pathogenesis of hepatic encephalopathy is undoubtedly multifactorial. Considerable evidence suggests that ammonia, primarily derived from the actions of gut bacteria, plays a central causal role in hepatic encephalopathy. 5 Recent research suggests that other bacteria-derived toxins in addition to ammonia may also contribute. For example, serum mercaptans derived from metabolism of methionine by colonic bacteria may be involved, as may blood-borne short-chain fatty acids such as butyrate, valerate, and phenols, which are produced by bacterial action on the amino acids tyrosine and phenylalanine. All of these substances have been found to be elevated in patients with chronic liver disease. 1,4 Therapeutic Management of Hepatic Encephalopathy Given the primary role of gut-derived ammonia in hepatic encephalopathy, most therapeutic approaches are directed at reducing bacterial production of ammonia and enhancing its elimination. 11 Therapeutic management consists primarily of control of precipitating factors, restriction of dietary protein, bowel cleansing, and administration of lactulose. 1,2,12,13 The identification and management of precipitating factors, most of which ultimately increase production or reduce elimination of ammonia, can improve hepatic encephalopathy. Specific precipitants are responsible VOL. 5 SUPPL REVIEWS IN GASTROENTEROLOGICAL DISORDERS S5

4 Managing Hepatic Encephalopathy continued for recurrent episodes or a worsening course of hepatic encephalopathy in the majority of patients with cirrhosis. 6 Particularly common precipitants of hepatic encephalopathy include gastrointestinal bleeding, infection, azotemia, and administration of sedatives or diuretic therapy. Restriction of dietary protein is intended to reduce the amount of substrate available for gut bacteria to degrade into ammonia. Protein reof the growth of Lactobacillus bifidus, a bacterial species deficient in ammonia-producing urease, would decrease ammonia production by colonic bacteria. 17 Lactulose appears to increase fecal nitrogen excretion by enhancing bacterial assimilation of ammonia and the conversion of ammonia to ammonium, which is excreted in the feces. 1 Lactulose, through its laxative effect, decreases intestinal transit time and thereby In clinical practice, the greatest therapeutic liability of lactulose is its association with bloating, nausea, flatulence, abdominal discomfort, and diarrhea. At high doses, lactulose may cause severe diarrhea with dehydration and acidosis. striction should be undertaken cautiously and for circumscribed periods of time because of the risk of nutritional compromise, which may worsen the overall clinical status in patients with cirrhosis. 5 Some cirrhotic patients, in fact, may require protein supplementation in order to maintain nitrogen balance. 12 Bowel cleansing with laxatives or nonabsorbable disaccharides (see below) is practiced on the basis of the assumption that reduction in colonic bacterial counts and colonic transit time decreases the amount of ammonia produced in and absorbed from the gut. 2 Although bowel cleansing has been shown to reduce intestinal and blood ammonia content, 14,15 its effects on neuropsychiatric symptoms have not been established. Lactulose ( -galactosido-fructose), a synthetic disaccharide, is currently the mainstay of treatment for hepatic encephalopathy. 16 Lactulose is hydrolyzed by colonic bacteria to lactic acid and acetic acids. 1,16-18 Part of the action of lactulose is attributed to its dose-related laxative effect. Lactulose was initially introduced with the rationale that its facilitation may reduce the time available for bacteria to produce and the intestines to absorb toxins. 12 Lactulose has been evaluated in a number of studies of patients with hepatic encephalopathy. Most of these studies were small, were of open-label design, and lacked a placebo control group. Of the 3 published placebocontrolled studies of lactulose in hepatic encephalopathy, only one a crossover study in 7 patients with chronic hepatic encephalopathy showed unequivocal benefit of lactulose over placebo. 19 On the other hand, a statistically significant benefit over placebo in clinical parameters was not shown in a parallel-group, placebo-controlled study involving 8 patients with chronic hepatic encephalopathy. 20 The third placebocontrolled study, conducted in 26 patients with acute hepatic encephalopathy, is difficult to interpret because data were not analyzed on an intent-to-treat basis. 21 Among patients who completed the study, however, lactulose compared with placebo statistically significantly improved clinical end points and reduced blood ammonia at the end of a 10-day treat- ment period. Despite the widespread use of lactulose in clinical practice, then, the clinical efficacy profile of the drug has not been established. This conclusion is supported by the results of a recently published Cochrane meta-analysis of 22 trials of nonabsorbable disaccharides in the treatment of hepatic encephalopathy. 22 The results show that nonabsorbable disaccharides compared with no intervention or placebo did not significantly affect mortality. Furthermore, nonabsorbable disaccharides were inferior to antibiotics in improving symptoms and reducing blood ammonia concentrations. The authors concluded that the evidence is insufficient to support or refute the use of nonabsorbable disaccharides for hepatic encephalopathy. In clinical practice, the greatest therapeutic liability of lactulose is its association with bloating, nausea, flatulence, abdominal discomfort, and diarrhea. 1,12 At high doses, lactulose may cause severe diarrhea with dehydration and acidosis. Besides gastrointestinal side effects, the excessive sweetness of lactulose, which is typically administered as a syrup, is poorly tolerated by some patients. 12 Lactitol, a disaccharide analogue of lactose in powder form, is more palatable than lactulose but is not available in the United States. 12 To correct various established and hypothesized abnormalities in hepatic encephalopathy, other therapeutic modalities have been tried; however, their efficacy has not been established, and none of them is widely used. For example, in attempts to reduce blood ammonia levels, ornithine-aspartate, a substrate for ureagenesis; zinc, a cofactor of urea cycle enzymes; and sodium benzoate, which increases ammonia excretion in urine, have been tried. 1,23 Likewise, exogenous branched-chain amino acids have been administered in an S6 VOL. 5 SUPPL REVIEWS IN GASTROENTEROLOGICAL DISORDERS

5 Managing Hepatic Encephalopathy attempt to correct the imbalance between blood-borne branched-chain amino acids and aromatic amino acids in patients with chronic liver disease. 1 The benzodiazepine receptor antagonist flumazenil, which inhibits GABAergic neurotransmission, has been tried for hepatic encephalopathy on the basis of the hypothesis that enhancement of GABAergic neurotransmission accounts for symptoms of hepatic encephalopathy. 1,24-27 Antibiotics in the Management of Hepatic Encephalopathy Unlike the therapeutic approaches described above, antibiotics can reduce or eliminate toxin-producing bacteria and prevent the production of ammonia at its source. The use of antibiotics to reduce or prevent cenoften used in hepatic encephalopathy (ie, neomycin, metronidazole, paromomycin, vancomycin), none effectively covers both aerobic and anaerobic organisms important in generating ammonia. Neomycin, paromomycin, and vancomycin have limited activity against gram-negative anaerobes, whereas metronidazole has limited activity against aerobes. Second, the clinical efficacy of currently available antibiotics, like that of lactulose, is not fully established in adequate studies. No large, well-controlled studies of neomycin, metronidazole, paromomycin, or vancomycin in the treatment of hepatic encephalopathy have been published. Neomycin, the best studied of these antibiotics, was not distinguishable from placebo in either of the two placebo-controlled studies conducted The use of antibiotics to reduce or prevent central nervous system exposure to ammonia is theoretically preferable to palliative approaches that address the harmful effects of ammonia once it is present in toxic concentrations in the central nervous system. tral nervous system exposure to ammonia is theoretically preferable to palliative approaches that address the harmful effects of ammonia once it is present in toxic concentrations in the central nervous system. Although the scientific rationale for the use of antibiotics in hepatic encephalopathy is well supported, they are underutilized for this disorder. Several factors appear to contribute to the underutilization of antibiotics. First, the spectrum of antibacterial activity of currently available antibiotics for hepatic encephalopathy may be too narrow to optimize ammonia-reducing efficacy. 28,29 Both aerobic and anaerobic colonic bacteria produce ammonia. 30 Of the currently available antibiotics most with the drug. 31,32 In the first placebocontrolled study, the combination of neomycin and lactulose (n 40) was not significantly better than placebo (n 40) at improving clinical status among 80 patients with acute hepatic encephalopathy. 31 In the second placebo-controlled study, also conducted in patients with acute hepatic encephalopathy, neomycin (n 20) did not differ from placebo (n 19) in time to resolution of hepatic encephalopathy, and the incidence of treatment failure and death by the fifth day of therapy was comparable between groups (2 patients in each group). 32 Metronidazole, vancomycin, and paromomycin have not been compared with placebo in the treatment of acute or chronic hepatic encephalopathy. Other studies of these antibiotics were small and employed openlabel designs or lactulose control groups. 28,33,34 In one of the bestdesigned of these studies, neomycin was associated with improvement comparable to that of lactulose in patients with acute hepatic encephalopathy in a randomized, doubleblind, parallel-group study that did not include a placebo group. 33 As the efficacy of lactulose versus placebo has not been established and as remission from acute episodes of hepatic encephalopathy is common, the data from this study are difficult to interpret. These data on the efficacy of antibiotics in hepatic encephalopathy do not necessarily suggest that these antibiotics are ineffective. Rather, the results of the antibiotic studies in hepatic encephalopathy whether positive or negative regarding antibiotic efficacy cannot be interpreted with confidence because the studies were generally small and poorly controlled, employed inconsistent methodologies, and did not account for variability in parameters such as precipitating factors or patients stage of disease. 2,4,5 The difficulty in conducting well-controlled studies in hepatic encephalopathy given the heterogeneity of the patient population is widely acknowledged. The lack of an evidence base on which to determine prescribing decisions arguably contributes substantially to reticence to employ antibiotics in the management of hepatic encephalopathy in clinical practice. The toxicities of currently available antibiotics preclude their first-line use for hepatic encephalopathy. 2 Although neomycin, vancomycin, and paromomycin are poorly absorbed, they reach the systemic circulation in sufficient concentrations to cause often serious side effects, including hearing loss, which can be permanent, and renal injury Like lactulose, VOL. 5 SUPPL REVIEWS IN GASTROENTEROLOGICAL DISORDERS S7

6 Managing Hepatic Encephalopathy continued these antibiotics may also cause diarrhea and intestinal malabsorption Because of its adverse tolerability profile in patients with hepatic encephalopathy, the absorbed antibiotic metronidazole is not recommended for use for longer than 2 weeks in these patients. 1,38 Metronidazole must be used cautiously in patients with neuropsychiatric diseases including hepatic encephalopathy because of its potential to cause neurotoxicity. Furthermore, the dosage of metronidazole requires adjustment in patients with severe liver disease. Patients using alcohol concomitantly with metronidazole or within 3 days after therapy with metronidazole may experience a reaction characterized by abdominal discomfort, vomiting, flushing, and headache. Metronidazole has also been reported to cause dose-dependent peripheral neuropathy. Conclusions: Future Directions in Antibiotic Therapy for Hepatic Encephalopathy The convergence of scientific evidence supports the important role of ammonia in the pathogenesis of hepatic encephalopathy and the potential usefulness of antibiotics in treatment. Antibiotics may be particularly promising in preventing the production of ammonia and other nitrogenous substances thereby, it is hypothesized, reducing exposure of the Although neomycin, vancomycin, and paromomycin are poorly absorbed, they reach the systemic circulation in sufficient concentrations to cause often serious side effects, including hearing loss, which can be permanent, and renal injury. central nervous system to ammonia that has bypassed hepatic clearance. In contrast, other pharmacologic approaches, such as administration of centrally active medications affecting neurotransmitter systems, are directed at mitigating the downstream effects of ammonia toxicity and do not prevent or reduce central nervous system exposure to neurotoxins. Although the scientific rationale for the use of antibiotics in hepatic encephalopathy is well founded, the clinical evidence for their benefits is rather limited. Antibiotics undoubtedly are associated with a decrease in intraluminal production of ammonia. However, currently available antibiotics are also associated with a variety of adverse effects. None of the antibiotics currently used for hepatic encephalopathy is adequately tolerated in the target patient population. The most widely used antibiotic, neomycin, is absorbed sufficiently in some patients to produce nephrotoxicity and auditory toxicity. The clinical evidence to date, then, does not support the first-line use of currently available antibiotics in the treatment of hepatic encephalopathy. The need for an effective, welltolerated pharmacotherapeutic agent that can limit the production of ammonia and other gut-derived toxins has stimulated the search for new treatments for hepatic encephalopathy. The data reviewed herein suggest that, to improve on current antibiotic offerings for hepatic encephalopathy, an antibiotic should Main Points Considerable evidence suggests that ammonia, primarily derived from the actions of gut bacteria, plays a central causal role in hepatic encephalopathy. Recent research suggests that other bacteria-derived toxins in addition to ammonia may also contribute. Given the primary role of gut-derived ammonia in hepatic encephalopathy, most therapeutic approaches are directed at reducing bacterial production of ammonia and enhancing its elimination. Therapeutic management consists primarily of control of precipitating factors, restriction of dietary protein, bowel cleansing, and administration of lactulose. Lactulose is currently the mainstay of treatment for hepatic encephalopathy, yet the clinical efficacy profile of the drug has not been established. In clinical practice, the greatest therapeutic liability of lactulose is its association with bloating, nausea, flatulence, abdominal discomfort, and diarrhea. At high doses, lactulose may cause severe diarrhea with dehydration and acidosis. Unlike other therapeutic approaches to hepatic encephalopathy, antibiotics can reduce or eliminate toxin-producing bacteria and prevent the production of ammonia at its source. Although the scientific rationale for the use of antibiotics in hepatic encephalopathy is well supported, they are underutilized for several reasons, including their narrow spectrum of activity, the lack of clinical evidence proving their efficacy, and their adverse effects. To improve on current antibiotic offerings for hepatic encephalopathy, an antibiotic should provide broad-spectrum coverage against both aerobic and anaerobic bacteria, effectively control neuropsychiatric signs and symptoms, and be extremely well tolerated in the target population. S8 VOL. 5 SUPPL REVIEWS IN GASTROENTEROLOGICAL DISORDERS

7 Managing Hepatic Encephalopathy Table 2 Properties of an Ideal Antibiotic for Hepatic Encephalopathy Provide broad-spectrum coverage against both aerobic and anaerobic bacteria Effectively control neuropsychiatric signs and symptoms Demonstrate good tolerability in the target population provide broad-spectrum coverage against both aerobic and anaerobic bacteria, effectively control neuropsychiatric signs and symptoms, and be extremely well tolerated in the target population (Table 2). The antibiotic preferably would not be absorbed from the gut so the possibility of systemic side effects would be minimized. An antibiotic fulfilling these criteria would constitute an advance in therapy for hepatic encephalopathy. References 1. Abou-Assi S, Vlahcevic ZR. Hepatic encephalopathy: metabolic consequence of cirrhosis often is reversible. Postgrad Med. 2001;109: Córdoba J, Blei AT. Treatment of hepatic encephalopathy. Am J Gastroenterol. 1997;92: Ong JP, Mullen KD. Hepatic encephalopathy. 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