Why is lactulose enema given in hepatic encephalopathy?

Uses

This drug is used by mouth or rectally to treat or prevent complications of liver disease (hepatic encephalopathy). It does not cure the problem, but may help to improve mental status. Lactulose is a colonic acidifier that works by decreasing the amount of ammonia in the blood. It is a man-made sugar solution.

If you are taking this medication by mouth for liver disease, take it usually 3-4 times a day or as directed by your doctor. To improve the taste, you may mix it into fruit juice, water, milk, or a soft dessert. The goal is to have 2-3 soft stools each day. Dosage is based on your medical condition and response to therapy (i.e., the number of soft stools each day).

If you are taking this medication by mouth for constipation, take it usually once daily or as directed by your doctor.

This medication can also be given rectally as an enema for liver disease. Mix the recommended amount of lactulose with 700 milliliters (24 ounces) of water or normal saline. Give the solution into the rectum and keep the liquid inside for 30-60 minutes as directed by your doctor. If you keep the enema inside for less than 30 minutes, repeat the dose unless directed otherwise.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time each day.

When this drug is given rectally for liver disease, an improvement in your mental status may occur in as little as 2 hours, but if you are taking this medication by mouth, it may take up to 24 to 48 hours. If you are using this medication for constipation, it may take up to 48 hours to have a bowel movement. Inform your doctor if your condition persists or worsens.

Side Effects

Gas, bloating, burping, stomach rumbling/pain, nausea, and cramps may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: diarrhea, vomiting, muscle cramps/weakness, irregular heartbeat, mental/mood changes, seizures.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

Before using lactulose, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: a low galactose diet (such as a diet that includes few or no milk products), certain other bowel problem (bowel obstruction), diabetes.

Do not take any laxative medications while using this drug. Frequent use or overuse of laxatives can cause dehydration. This is especially likely to occur in children or the elderly. Contact your doctor right away if you develop any of the following symptoms of dehydration: muscle weakness, muscle cramps, dizziness.

Before having surgery or other procedures (such as electrocautery), tell your doctor or surgeon that you are using this medication.

This medication contains different sugars. If you have diabetes, this medication may affect your blood sugar. Check your blood sugar regularly as directed and share the results with your doctor. Your doctor may need to adjust your diabetes medication, exercise program, or diet.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug are: antacids containing aluminum and/or magnesium, other laxatives (such as cleansing enemas with soap suds).

Does Lactulose (For Encephalopathy) Solution interact with other drugs you are taking?

Overdose

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe stomach cramps, diarrhea.

Notes

If you are using this medication for liver disease, your doctor may direct you to follow a low-protein diet. Follow any dietary guidelines recommended by your doctor or dietician.

Do not share this product with others.

If you use this product for an extended time, laboratory and/or medical tests (such as blood mineral levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Missed Dose

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

Storage

Store between 36-86 degrees F (2-30 degrees C) away from light and moisture. Do not freeze because this will make the medication too thick to pour. If it becomes frozen, warm it to room temperature until it is pourable again. A normal darkening of color may occur. If too much darkening occurs and you cannot swallow it, discard the medication and get a refill. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

Selected from data included with permission and copyrighted by First Databank, Inc. This copyrighted material has been downloaded from a licensed data provider and is not for distribution, except as may be authorized by the applicable terms of use.

CONDITIONS OF USE: The information in this database is intended to supplement, not substitute for, the expertise and judgment of healthcare professionals. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for you or anyone else. A healthcare professional should be consulted before taking any drug, changing any diet or commencing or discontinuing any course of treatment.

The approach to a patient with hepatic encephalopathy depends upon the severity of the mental status changes and upon the certainty of the diagnosis. As an example, a patient with known cirrhosis and mild complaints of decreased concentration might be served best by an empiric trial of rifaximin or lactulose and a follow-up office visit to check its effect. However, a patient presenting to the emergency department with severe hepatic encephalopathy requires a different approach. General management recommendations include the following:

• Exclude nonhepatic causes of altered mental function.

• Consider checking an arterial ammonia level in the initial assessment of a hospitalized patient with cirrhosis and with impaired mental function. Ammonia levels have less use in a stable outpatient.

• Precipitants of hepatic encephalopathy, such as hypovolemia, metabolic disturbances, gastrointestinal bleeding, infection, and constipation, should be corrected.

• Avoid medications that depress central nervous system function, especially benzodiazepines. Patients with severe agitation and hepatic encephalopathy may receive haloperidol as a sedative. Treating patients who present with coexisting alcohol withdrawal and hepatic encephalopathy is particularly challenging. These patients may require therapy with benzodiazepines in conjunction with lactulose and other medical therapies for hepatic encephalopathy.

• Patients with severe encephalopathy (ie, grade 3 or 4) who are at risk for aspiration should undergo prophylactic endotracheal intubation. They are optimally managed in the intensive care unit.

Most current therapies are designed to treat hyperammonemia that is a hallmark of most cases of hepatic encephalopathy.

Diet

In the late 19th century, it was recognized that the feeding of a high-protein diet to dogs that had undergone portosystemic shunt surgery could produce symptoms of abnormal coordination and stupor in the treated animals.

In the 20th century, low-protein diets were routinely recommended for patients with cirrhosis, in the hope of decreasing intestinal ammonia production and in preventing exacerbations of hepatic encephalopathy. An obvious consequence was the worsening of preexisting protein-energy malnutrition. Protein restriction may be appropriate in some patients immediately following a severe flare of symptoms (ie, episodic hepatic encephalopathy). However, protein restriction is rarely justified in patients with cirrhosis and persistent hepatic encephalopathy. Indeed, malnutrition is a more serious clinical problem than hepatic encephalopathy for many of these patients.

In the author's experience, it is an infrequent patient who is intolerant of a diet high in protein. Most patients with mild chronic hepatic encephalopathy tolerate more than 60-80 g of protein per day. Furthermore, one study administered a protein-rich diet (>1.2 g/kg/d) to patients with advanced disease awaiting liver transplantation, without inducing a flare of encephalopathy symptoms. [40] Another study randomized patients with severe episodic encephalopathy to either a low-protein diet or a high-protein diet, administered via nasogastric tube. [41] All patients received the same regimen of neomycin per nasogastric tube. Mental function improved at the same rate in both treatment groups. Importantly, patients receiving the low-protein diet had evidence of increased protein breakdown during the duration of the study.

Diets containing vegetable proteins appear to be better tolerated than diets rich in animal proteins, especially proteins derived from red meats. This may be because of increased content of dietary fiber, a natural cathartic, and decreased levels of aromatic amino acids. Aromatic amino acids, as precursors of the false neurotransmitters tyramine and octopamine, are thought to inhibit dopaminergic neurotransmission and worsen hepatic encephalopathy.

The author recommends that patients consume well-cooked chicken and fish in addition to vegetable proteins. Malnourished patients are encouraged to add commercially available liquid nutritional supplements to their diet. Patients rarely require specialized treatment with oral or enteral supplements rich in branched-chain amino acids.

To evaluate the beneficial and harmful effects of branched-chain amino acids (BCAA) versus any control intervention for people with hepatic encephalopathy, Gluud and colleagues conducted a systematic review involving 16 randomized clinical trials that included 827 participants with hepatic encephalopathy. Primary outcomes included mortality (all cause), hepatic encephalopathy (number of people without improved manifestations of hepatic encephalopathy), and adverse events. The control groups received placebo/no intervention, diets, lactulose, or neomycin. In 15 trials, all participants had cirrhosis. Analyses showed that BCAA had a beneficial effect on hepatic encephalopathy. The authors found no effect of BCAA on mortality, quality of life, or nutritional parameters, but they recommended additional trials to evaluate these outcomes. [42]

Cathartics

Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable disaccharides that have been in common clinical use since the early 1970s (the latter is not available in the United States). They are degraded by intestinal bacteria to lactic acid and other organic acids.

Lactulose appears to inhibit intestinal ammonia production by a number of mechanisms. The conversion of lactulose to lactic acid and acetic acid results in the acidification of the gut lumen. [43, 44] This favors conversion of ammonia (NH3) to ammonium (NH4+); owing to the resultant relative impermeability of the membrane, the NH4+ ions are not easily absorbed, thereby remaining trapped in the colonic lumen, and there is a reduction in plasma NH3. [43, 44, 45] Gut acidification inhibits ammoniagenic coliform bacteria, leading to increased levels of nonammoniagenic lactobacilli. [43] Lactulose also works as a cathartic, reducing colonic bacterial load.

Initial lactulose dosing is 30 mL orally, daily or twice daily. The dose may be increased as tolerated. Patients should be instructed to reduce lactulose dosing in the event of diarrhea, abdominal cramping, or bloating. Patients should take sufficient lactulose as to have 2-4 loose stools per day.

Great care must be taken when prescribing lactulose. Overdosage can result in ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. Hypovolemia may be sufficiently severe as to actually induce a flare of encephalopathy symptoms.

Higher doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by nasogastric tube to patients hospitalized with severe hepatic encephalopathy. Lactulose may be administered as an enema to patients who are comatose and unable to take the medication by mouth. The recommended dosing is 300 mL lactulose plus 700 mL water, administered as a retention enema every 4 hours as needed.

Lactulose has been the subject of dozens of clinical trials over almost four decades. Many small trials demonstrated the medication's efficacy in the treatment of hepatic encephalopathy. A controversial meta-analysis published in 2004 contradicted these trials and most physicians' clinical experiences. [46] When assessing high-quality randomized trials, lactulose was no more effective than placebo at improving encephalopathy symptoms. In trials comparing lactulose to an antibiotic (eg, neomycin, rifaximin), lactulose was actually inferior to antibiotic therapy.

In subsequent years, multiple randomized trials have reinvestigated the efficacy of lactulose.

In patients with minimal hepatic encephalopathy, lactulose was more effective than placebo in terms of improving patient performance on psychometric testing. [47, 48]

Lactulose was studied in large randomized trials as secondary prevention against recurrent overt encephalopathy. [49, 50] In the study by Sharma et al, patients who were recovering from hepatic encephalopathy were randomized to receive lactulose (n = 61) or placebo (n = 64). Over a median follow-up of 14 months, 12 patients (19.6%) in the lactulose group developed overt hepatic encephalopathy as compared with 30 patients (46.8%) in the placebo group (P = 0.001). The authors concluded that lactulose effectively prevented the recurrence of overt hepatic encephalopathy in patients with cirrhosis. [49]

Lactulose also appeared to be effective as primary prophylaxis against the development of overt hepatic encephalopathy, [51] although few physicians in the United States would advocate the use of lactulose for this indication.

An updated meta-analysis published in 2013 included these studies and affirmed the utility of lactulose in the management of hepatic encephalopathy. [52]

Antibiotics

Neomycin and other antibiotics, such as metronidazole, oral vancomycin, paromomycin, and oral quinolones, are administered in an effort to decrease the colonic concentration of ammoniagenic bacteria. Initial neomycin dosing is 250 mg orally 2-4 times a day. Doses as high as 4000 mg/d may be administered. Neomycin is usually reserved as a second-line agent, after initiation of treatment with lactulose. Long-term treatment with this oral aminoglycoside runs the risks of inducing ototoxicity and nephrotoxicity because of some systemic absorption.

Rifaximin (Xifaxan), a nonabsorbable derivative of rifampin, has been used in Europe for more than 20 years for a wide variety of gastrointestinal indications. Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactitol at improving hepatic encephalopathy symptoms. [46, 53, 54] Similarly, rifaximin was as effective as neomycin and paromomycin. Rifaximin had a tolerability profile comparable to placebo. It was better tolerated than both the cathartics and the other nonabsorbable antibiotics. A potential mechanism for rifaximin's clinical activity is its effects on the metabolic function of the gut microbiota, rather than a change in the relative bacterial abundance. [55]

In 2004, rifaximin received approval by the FDA in the United States for the treatment of travelers' diarrhea. In 2005, it received orphan drug status as a treatment for hepatic encephalopathy. In March 2010, rifaximin was approved by the FDA to reduce recurrence of hepatic encephalopathy. The approval was based on a phase 3 clinical trial conducted by Bass et al. [56]

Bass et al evaluated rifaximin’s ability to reduce the risk of recurrent hepatic encephalopathy (HE). [56] In this double-blind, placebo-controlled, multinational, phase 3 clinical trial, 299 patients received either rifaximin 550 mg or placebo BID. Each group also received lactulose. Breakthrough episodes of HE occurred in 22% of patients treated with rifaximin and 46% of patients with placebo (P< 0.001). HE-related hospitalization occurred in 14% of patients treated with rifaximin and 23% of patients treated with placebo (P = 0.01).

Peripheral edema and nausea are described in some rifaximin-treated patients. There are also questions whether long-term treatment with rifaximin can induce microbial resistance. Thus far, microbial resistance has not been reported in patients using the medication. It remains unclear whether diarrhea caused by Clostridium difficile occurs at a higher rate in rifaximin-treated patients than untreated patients. In the study by Bass et al, two rifaximin-treated patients and no placebo-treated patients developed C difficile infection. [56]

Rifaximin was also examined in patients with minimal hepatic encephalopathy. In a large study by Sidhu et al, rifaximin was more effective than placebo in terms of improving patient performance on psychometric testing and in terms of improving health-related quality of life. [57]

L-ornithine L-aspartate (LOLA)

LOLA (Hepa-Merz) is available in Europe in both intravenous formulations and oral formulations. It is not available in the United States. LOLA is a stable salt of the two constituent amino acids. L-ornithine stimulates the urea cycle, with resulting loss of ammonia. Both l-ornithine and l-aspartate are substrates for glutamate transaminase. Their administration results in increased glutamate levels. Ammonia is subsequently used in the conversion of glutamate to glutamine by glutamine synthetase. LOLA was found to be effective in treating hepatic encephalopathy in a number of European trials. [58, 59]

Zinc

Zinc deficiency is common in cirrhosis. Even in patients who are not zinc deficient, zinc administration has the potential to improve hyperammonemia by increasing the activity of ornithine transcarbamylase, an enzyme in the urea cycle. The subsequent increase in ureagenesis results in the loss of ammonia ions.

Zinc sulfate and zinc acetate have been used at a dose of 600 mg orally every day in clinical trials. Hepatic encephalopathy improved in two studies [60] ; there was no improvement in mental function in two other studies. [61]

Meena et al evaluated the correlation between low serum zinc levels in 75 patients with decompensated chronic liver disease (DCLD) and various stages of hepatic encephalopathy. There was a statistically significant association between low serum zinc level and the grade of HE (P = 0.001) or class of liver cirrhosis (P = 0.001). Additional studies are needed to establish the role of correcting hypozincemia to prevent worsening of cirrhosis and development of encephalopathy. [62]

Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate, glycerol phenylbutyrate

Sodium benzoate interacts with glycine to form hippurate. The subsequent renal excretion of hippurate results in the loss of ammonia ions. Dosing of sodium benzoate at 5 g orally twice a day can effectively control hepatic encephalopathy. [63] Use of the medication is limited by the risk of salt overload and by its unpleasant taste. The medication, also used as a food preservative, is available through many specialty chemical manufacturers throughout the United States. The author has limited its use to patients with severe encephalopathy symptoms. However, in the author’s opinion, doses of sodium benzoate as low as 2.5 g orally three times per week significantly improved mental function in outpatients who had persistent encephalopathy symptoms despite cotherapy with lactulose and rifaximin.

Sodium phenylbutyrate is converted to phenylacetate. Phenylacetate, in turn, reacts with glutamine to form phenylacetylglutamine. This chemical is subsequently excreted in the urine, with the loss of ammonia ions. Sodium phenylbutyrate (Buphenyl), intravenous sodium phenylacetate in combination with sodium benzoate (Ammonul), and glycerol phenylbutyrate (Ravicti) are approved by the FDA for the treatment of hyperammonemia associated with urea cycle disorders. [64] The latter is currently in clinical trials in cirrhotic patients with hepatic encephalopathy. [65]

In a phase II trial involving 178 patients with cirrhosis (including 59 already taking rifaximin) who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months, glycerol phenylbutyrate (GPB), at a dose of 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event, time to first event, and total events. [66] In addition, GPB was associated with fewer HE hospitalizations. For patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event, time to first event, and total events. Plasma ammonia was significantly lower in patients on GPB than in patients on placebo. Adverse events occurred in a similar proportion of patients in the GPB and placebo groups. The authors concluded that the results implicated ammonia in the pathogenesis of HE and suggested that GPB had therapeutic potential in this patient population. [66]

L-carnitine

L-carnitine improved hepatic encephalopathy symptoms in several small studies of patients with cirrhosis. [67] Whether the medication works by improving blood ammonia levels or whether it works centrally perhaps by decreasing brain ammonia uptake remains unclear. [68]

Sleep disturbances are more common in patients with cirrhosis than in control subjects. Whether or not this relates to hepatic encephalopathy is unclear. A trial compared the histamine H1 blocker hydroxyzine with placebo in patients with cirrhosis and minimal hepatic encephalopathy. [69] Sleep efficiency and the patients' subjective quality of sleep improved in patients receiving hydroxyzine (25 mg) at bedtime. However, there was no accompanying improvement in cognition, as measured by neurophysiologic tests. The authors urged caution when prescribing hydroxyzine, on account of the risk of worsening encephalopathy in some patients.

Hepatic encephalopathy is seen in about 1 in 3 patients who undergo the creation of a transjugular intrahepatic portosystemic shunt (TIPS). Typically, post-TIPS encephalopathy symptoms are well controlled with the use of rifaximin or lactulose. However, post-TIPS encephalopathy symptoms can be profound in some instances. In a study by Fanelli et al, 12 of 189 patients undergoing TIPS developed encephalopathy that was refractory to conventional therapy with lactulose. These patients subsequently underwent placement of an hourglass-shaped balloon-expandable polytetrafluoroethylene (ePTFE) stent-graft inside the original shunt. Encephalopathy symptoms resolved in all of the patients over the next 18-26 hours. [70] Of course, such a procedure is not expected to improve a patient's overall condition. At the end of a mean of 74 weeks of follow-up, only 5 of the 12 patients remained alive and in good clinical condition.

Trebicka et al studied the outcomes of diameter of covered, self-expandable nitinol stents in patients with a TIPS. Of 185 patients, 53 received 8 mm stents and the remaining received 10 mm stents. Patients who received 8 mm stents survived significantly longer than patients who received 10 mm stents, regardless whether they were fully dilated or underdilated. The authors concluded that the 8 mm stent is associated with a prolonged survival compared to 10 mm stents, independent of liver specific prognostic criteria. [71]