[90] Lack of effect of lactulose should prompt a clinical search for unrecognized precipitating factors and competing causes for the brain impairment. Though it is assumed that the prebiotic effects (the drug being a nondigestible substance that promotes the growth of beneficial microorganisms in

the intestines) and acidifying nature of lactulose have an additional benefit beyond the laxative effect, culture-independent studies have not borne those out.[75, 91] In addition, most recent trials on lactulose have been open label in nature. Cost considerations alone add to the argument in support of lactulose.[92] In some centers, lactitol is preferred to lactulose, based on small meta-analyses of even smaller trials.[93, 94] In populations with a high prevalence of lactose intolerance, the use of lactose has been suggested.[95] However, the only trial to show that stool-acidifying enemas (lactose and lactulose) Peptide 17 price were superior to tap-water enemas was underpowered.[96] The use of polyethylene

glycol preparation[97] needs further validation. The dosing of lactulose should be initiated[98] when the three first elements of the four-pronged approach are completed, with 25 mL of lactulose syrup every 1-2 hours until at least two soft or loose bowel movements per day are produced. Subsequently, the dosing is titrated to maintain two to three bowel movements per day. This dose reduction should be implemented. It is a misconception that lack of effect of smaller amounts of lactulose is remedied by much larger doses. There is BMS-354825 price a danger for overuse of lactulose leading to complications, such as aspiration, dehydration, MCE hypernatremia, and severe perianal skin irritation, and overuse can even precipitate HE.[99] Rifaximin has been used for the therapy of HE in a number of trials[100] comparing it with placebo, other antibiotics, nonabsorbable disaccharides, and in dose-ranging studies. These trials showed effect of rifaximin that was equivalent or superior to the compared agents with good tolerability. Long-term cyclical therapy over 3-6 months with rifaximin for patients with OHE has also been studied in three trials (two compared

to nonabsorbable disaccharides and one against neomycin) showing equivalence in cognitive improvement and ammonia lowering. A multinational study[101] with patients having two earlier OHE bouts to maintain remission showed the superiority of rifaximin versus placebo (in the background of 91% lactulose use). No solid data support the use of rifaximin alone. Many drugs have been used for treatment of HE, but data to support their use are limited, preliminary, or lacking. However, most of these drugs can safely be used despite their limited proven efficacy. An updated meta-analysis of eight randomized, controlled trials (RCTs) indicated that oral BCAA-enriched formulations improve the manifestations of episodic HE whether OHE or MHE.[102, 130] There is no effect of IV BCAA on the episodic bout of HE.