Lactulose therapy

In patients taking lactulose therapy, titrate the dose to two to four soft bowel movements daily. 

Do not take other laxatives while on lactulose therapy... 

Sodium benzoate Sodium benzoate has already been successfully used to treat congenital enzymatic defects of the urea synthesis (M. L. Batshaw et at, 1981). In HE, the administration of sodium benzoate or sodium phenylacetate (each 10 g/day) achieved clinical success equivalent to lactulose therapy in ca. 80% of cases. (122, 144, 159) These substances (which are cheap and practically free of side effects) lead to an increased excretion of nitrogen through the conjugation of glycine and glutamine, whereby ammonium is bound as hippuric acid and excreted renally (bypassing the urea cycle). 

Metronidazole Up to 99% of the intestinal anaerobes that are largely responsible for the bacterial formation of ammonia are affected by metronizadole. Its efficacy corresponds to that of neomycin and paromomycin. The mode of action is still unresolved. The dosage is 3(-4) X 0.4 g/day with subsequent reduction to 2 x 0.4 g/day provided two or three stools can be produced each day. When used for longer periods, peripheral neuropathies can occur. For this reason, initial treatment with metronidazole should be replaced as soon as possible by long-term lactulose therapy. (147)... 

Vancomycin is known as a reserve antibiotic. It has been successfully used in patients with lactulose therapy failure. (160) Above all, vancomycin reduces the bacteroides population. The recommended dosage is 4 x 0.5 g/day. 

The patient is instructed to record his morning body weight (always under the same conditions) every day on a documentation sheet (E. Kuntz, 1989) as well as the frequency of stools (e.g. under lactulose therapy) and to enter a handwriting specimen (usual way of writing the first and last name) every one or two days. (s. fig. 15.3) This documentation sheet is deemed to be a useful and efficient instrument (which can be kept as a medical record) in the control and follow-up of a chronic course of disease. An ancillary benefit is that the extent to which the patient is cooperating can also be deduced from the accuracy of the entries made. (s. p. 275)... 

Antibiotic therapy with either metronidazole or neomycin is reserved for patients who have not responded to diet and lactulose therapy, where the combination may provide additive effects and improved chnical response. Zinc supplementation at a dose of 600 mg/day is recommended for long-term management in patients with cirrhosis who are zinc deficient. 

Hypokalemia is common in the patient with liver failure who has normal renal function. Poor nutritional intake and vomiting may initiate this disorder. Severe vomiting may lead to volume contraction metabolic alkalosis, with increased renal excretion of potassium. Secondary hyperaldosteronism, seen in the liver failure patient with intravascular depletion, also increases renal excretion of potassium. Loop diuretic therapy causes increased renal excretion of potassium, whereas diarrhea from lactulose therapy increases fecal excretion of potassium. All these conditions can lead to profound hypokalemia. Therefore, potassium requirements in the liver failure patient receiving specialized nutritional support often are increased substantially. 

Antibiotics like neomycin or metronidazole are administered either when an episode of HE arises or chronically to avoid the development of clinically overt HE. In the past, neomycin was the most used antibiotic. There is increasing evidence, however, that rifaximin has a more favorable benefit risk ratio in the treatment of HE (Leevy and Phillips, 2007 Mas et al., 2003). While neuro- and nephrotoxicity have to be considered in neomycin rifaximin is well-tolerated. Recently Leevy and Phillips (2007) showed in 145 patients that the frequency and grade of HE was lower with rifaximin therapy compared to lactulose therapy, and that with rifaximin therapy the patients were less often hospitalized than with 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... 

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. 

Treatment approaches include (1) reduction of blood ammonia concentrations by dietary restrictions, and drug therapy aimed at inhibiting ammonia production or enhancing its removal (lactulose and antibiotics) and (2) inhibition of y-aminobutyric acid-benzodiazepine receptors by flumazenil. 

Antibiotic therapy with metronidazole or neomycin is reserved for patients who have not responded to diet and lactulose. 

If additional therapy is warranted, the use of supplemental fiber with or without a stool softener is appropriate. Lactulose, sorbitol, bisacodyl, or senna can be used occasionally. 

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

Treatment approaches include (1) reduction of blood ammonia concentrations by dietary restrictions, and drug therapy aimed at inhibiting ammonia production or enhancing its removal (lactulose and antibiotics) and (2) inhibition of y-aminobutyric acid-benzodiazepine receptors by flumazenil. Approaches to reducing blood ammonia concentrations include In patients with acute HE, limit protein intake to 10 to 20 g/day while maintaining the total caloric intake. Protein intake can be titrated by increasing 10 to 20 g/day every 3 to 5 days to a total of 0.8 to 1 g/kg/day. With chronic HE, restrict protein intake to 40 g/day. 

Since 1966, lactulose has been considered the therapy of choice in the treatment (and prophylaxis) of HE. (s. 

Intestinal detoxiflcation by means of lactulose, which, among other things, delays the production and/or portal uptake of endotoxins, is another important therapy step. 

Lactulose is administered as long-term therapy. The indications are derived from its modes of action, (s. tab. 40.9)... 

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. 

The use of lactulose, a nonabsorbable disaccharide, (and lactitol, not available in the United States) is standard therapy for both acute and chronic HE. Lactulose, when administered orally, passes through the gastrointestinal tract and reaches the colon unchanged. For patients unable to take lactulose orally or via tube administration it may be administered as an enema. In the colon, lactulose lowers colonic pH and exerts a cathartic effect. Fermentation of lactulose by bacteria present in the colon results in the production of organic acids, decreasing colonic pH to approximately 5. ... 

Inhibiting the activity of urease-producing bacteria by using neomycin, metronidazole, or vancomycin can decrease production of ammonia. Neomycin at doses of 2 to 8 g daily in divided oral doses results in clinical improvement in as many as 80% of patients. At these doses, however, absorption is 1% to 5% and can result in irreversible ototoxicity and nephrotoxicity. As such, even though efficacy is equivalent to lactulose, neomycin should not be first-line therapy. Metronidazole produces response rates similar to neomycin, but side effects, particularly gastrointestinal, limit its use. In patients... 

BCAA products have not universally improved nitrogen balance. Standard amino acid mixtures can be used successfully without worsening encephalopathy. Studies examining improvement in encephalopathy or mortality rates with use of these modified amino acids have yielded conflicting results. This, coupled with the increased cost of these products, has led most clinicians to reserve these products for patients with severe encephalopathy who decompensate on standard amino acids despite continued lactulose-neomycin therapy. 

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. 

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