Hepatic encephalopathy lactulose

Lactulose is the foundation of pharmacologic therapy to prevent and treat hepatic encephalopathy because its unique mechanism binds ammonia in the gut and facilitates its excretion. 

Lactulose is the foundation of pharmacologic therapy to prevent and treat hepatic encephalopathy. It is a non-digestible synthetic disaccharide laxative that is hydrolyzed in the gut to an osmotically-active compound that draws water into the colon and stimulates defecation. Lactulose also lowers colonic pH, which favors the conversion of ammonia (NH3) to ammonium (NHf).48 Ammonium is ionic and cannot cross back into systemic circulation it is eliminated in the feces. Lactulose is usually initiated at 15 to 30 mL two to three times per day and titrated to a therapeutic goal of two to four soft bowel movements daily.20 49 50... 

Lanthier PL, Morgan MY Lactitol in the treatment of chronic hepatic encephalopathy An open comparison with lactulose. Gut 1985 26 415-420. 

Tarao K, Ikeda T, Hayashi K, Sakurai I A Successful use of vancomycin hydrochloride in the treatment of lactulose-resistant chronic hepatic encephalopathy. J Gastroenterol Hepatol 1989 4 284-286. 

Massa MD, Vallerino MD, Dodero MD Treatment of hepatic encephalopathy with rifaximin Double blind, double dummy study versus lactulose. Eur J Clin Res 1993 4 7-18. 

Bucci L, Palmieri GC Double-blind, doubledummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res Opin 1993 13 109—118. 

After the submission of the manuscript three interesting papers [1-3] dealing with the management of hepatic encephalopathy have been published. A Cochrane systematic review [1] evaluating 30 randomized controlled trials did conclude that antibiotics appear to be superior to nonabsorbable disaccharides in improving symptoms of portal systemic encephalopathy. The authors also emphasized that there is insufficient high-quality evidence to support the use of lactulose or lactitol. A combination of a disaccharide and an antibiotic has been suggested, but not consistently demonstrated to be beneficial [2]. Finally, the use of probiotics has been proposed [3], whose administration could actually follow that of antibiotics. 

Dasarathy S Role of gut bacteria in the therapy of hepatic encephalopathy with lactulose and antibiotics. Indian J Gastroenterol 2003 22(suppl 2) S50-S53. 

Hepatic encephalopathy 30-45 mL PO tid-qid, or 250 mL PR qid [300 mL of lactulose combined with 700 mL of water] instill via rectal tube, then clamp tube for 45 min. 

Osmotic laxatives (e.g., lactulose, sorbitol) are poorly absorbed or nonabsorbable compounds that draw additional fluid into the GI tract. Lumen osmolality increases, and fluid movement occurs secondary to osmotic pressure. Lactulose is a synthetic disaccharide that is poorly absorbed from the GI tract, since no mammalian enzyme is capable of hydrolyzing it to its monosaccharide components. It therefore reaches the colon unchanged and is metabolized by colonic bacteria to lactic acid and to small quantities of formic and acetic acids. Since lactulose does contain galactose, it is contraindicated in patients who require a galactose-free diet. Metabolism of lactulose by intestinal bacteria may result in increased formation of intraluminal gas and abdominal distention. Lactulose is also used in the treatment of hepatic encephalopathy. 

This is a semisynthetic disaccharide which is not absorbed from the GI tract. It produces an osmotic diarrhoea of low pH, and discourages the proliferation of ammonia-producing bacteria. It is therefore useful in the treatment of hepatic encephalopathy. Osmotic laxatives like lactulose, sorbitol, and lactilol rarely cause significant adverse effects. Glycerol suppositories are useful in softening and lubricating passage of inspissated faeces. 

Lactulose (Constulose, Generlac, Enulose, Others) [Laxative/ Osmotic] Uses Hepatic encephalopathy constipation Action Acidifies the colon, allows ammonia to diffuse into colon Dose Acute hepatic encephalopathy. 30-45 mLPO qlh until soft stools, then tid-qid Chronic laxative therapy 30-45 mL... 

Suppression of bowel flora is thought by some to be useful in hepatic encephalopathy. Here, absorption of products of bacterial breakdown of protein (ammonium, amines) in the intestine lead to cerebral symptoms and even to coma. In acute coma, neomycin 6 g/d should be given by gastric tube as prophylaxis, 1-4 g/d may be given to patients with protein intolerance who fail to respond to dietary protein restriction (see also lactulose, p. 640). 

Loguercio, C., Abbiati, R., Rinaldi, M., Romano, A., Dei VeccMo Bianco, C., Coitori, M. Long-term effects of Enterococcus faecium SF 68 versus lactulose in the treatment of patients with cirrhosis and grade 1-2 hepatic encephalopathy. X Hepatol. 1995 23 39-46... 

McClain, C.J., Potter, T.J., Kromhout, J.R, Zieve, L. The effect of lactulose on psychomotor performance tests in alcoholic cirrhotics without overt hepatic encephalopathy. J. Clin. Gastroenterol. 1984 6 325-329... 

Riggio, O., Balducci, G., Ariosto, F., Merli, M., Tremlterra, S., Ziparo, V., Capocaccia, L. Lactitol in the treatment of chronic hepatic encephalopathy — a randomized cross-over comparison with lactulose. Hepato-Gastroenterol 1990 37 524-527... 

Watanabe, A., Sakai, T., Sato, S., Imai, F., Ohio, M., Arakawa, Y., Tod G., KobayasU, K., Muto, Y., Tsujii, T., Kawasaki, H., Okita, K., Tanikawa, K., Fujiyama, S., Shimada, S. Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 1997 26 1410-1414... 

Long-term application of lactulose, possibly in shortterm combination with neomycin or paromomycin, is recommended. This is especially true when there are signs of an onset of hepatic encephalopathy. 

Self-monltorlng on the part of the patient makes it possible to identify the beginning of water accumulation in the organism (> 1 litre), a reduced lactulose effect (which is inadequate for intestinal detoxification) and/or a latent phase of hepatic encephalopathy. In such cases, immediate outpatient treatment is generally reliable and swift in its therapeutic success. 

There has been a systematic review of 30 randomized comparisons in hepatic encephalopathy of lactulose or lactitol with no intervention, placebo, or antibiotics and comparisons of lactulose with lactitol (39). Compared with placebo or no intervention, non-absorbable disaccharides had no statistically significant effect on mortahty, but appeared to reduce the risk of no improvement of hepatic encephalopathy. However, this result might have reflected bias, owing to the poor quality of the majority of the studies. 

Shibasaki K, Tsuboi Y, Hasegawa K, Toshima M, Soga K. Effects of long-term administration of lactitol or lactulose in cirrhotic patients with chronic hepatic encephalopathy. Ther Res 2001 22 899-907. 

Treatment is largely empirical, based on observations that intestinal bacteria and protein loads in the intestinal tract are important in the symptoms of hepatic encephalopathy. Lactulose has long been recognized to reduce the symptoms in chronic hepatic encephalopathy. Antibiotic treatment with a nonabsorbable antibiotic such as neomycin reduces the number of bacteria and is especially helpful in patients with GI bleeding. Protein reduction in the diet also improves encephalopathy reducing dietary protein to the less than 40g/day often needed to improve symptoms may compromise nutrition. Patients with acute encephalopathy require... 

The mainstay of therapy of hepatic encephalopathy involves therapy to lower blood ammonia concentrations, and includes diet therapy, lactulose, and antibiotics alone or in combination with lactulose. 

Lactulose also is used to treat hepatic encephalopathy. Patients with severe liver disease have an impaired capacity to detoxify ammonia coming from the colon, where it is produced by bacterial metabolism of fecal urea. The drop in luminal pH that accompanies hydrolysis to short-chain fatty acids in the colon results in trapping of the ammonia by its conversion to the polar ammonium ion. Combined with the increases in colonic transit, this therapy lowers circulating ammonia levels. The therapeutic goal in this condition is to give sufficient amounts of lactulose (usually 20 to 30 g, 3 to 4 times per day) to produce two to three soft stools a day with a pH of 5 to 5.5. 

The oral administration of neomycin (usually in combination with erythromycin base) has been employed primarily for preparation of the bowel for surgery. For therapy of hepatic encephalopathy, a daily dose of 4 to 12 g (in divided doses) by mouth is given, provided that renal function is normal. Because renal insufficiency is a complication of hepatic failure and neomycin is nephrotoxic, it is used rarely for this indication. Lactulose is a much less toxic agent and is preferred. 

Fortunately, bed rest, rehydration, parenteral nutrition, and therapy directed at decreasing the production of toxins that result from bacterial degradation of nitrogenous substrates in the gut lumen (e.g., administration of lactulose, which reduces gut ammonia levels by a variety of mechanisms, the use of enemas and antibiotics to decrease the intestinal flora, a low-protein diet) prevented Percy Veere from progressing to the later stages of hepatic encephalopathy. As with most patients who survive an episode of fulminant hepatic failure, recovery to his previous state of health occurred over the next 3 months. Percy s liver function studies returned to normal, and a follow-up liver biopsy showed no histologic abnormalities. 

Patil DH, Westaby D, Mahida YR, Palmer KR, Rees Clark ML, Dawson AM, SiUc DBA. Comparative modes of action of lactitol and lactulose in tiie treatment of hepatic encephalopathy. G f(1987) 28, 255-9. 

Lactitol has been shown to be as effective as lactulose for treating hepatic encephalopathy (Morgan et al., 1989 Morgan and Hawley 1987). Conamon side effects of the disaccharides are flatulence and abdominal cramping. 

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