You have a Grade III encephalopathy patient. You’ve started the Lactulose, and you’re waiting. But 48 hours later, they are still incoherent! Sounds like a commonly encountered scenario!

Hepatic encephalopathy is a topic that seems everyone thinks they know how to manage, yet many fall into one or more of these traps.

Mistake 1: Treating the Ammonia Number Instead of the Patient

An elevated serum ammonia level without clinical signs of HE is NOT an indication for treatment. HE is a clinical, not a lab diagnosis.

Quite often, I see ammonia is ordered in the ED, it comes back elevated, and lactulose is automatically ordered despite the lack of any symptoms or signs to suggest encephalopathy.

The American Association for the Study of Liver Diseases (AASLD) specifically advises against routine ammonia measurement for diagnosis or trending response to treatment of hepatic encephalopathy, as ammonia levels are variable within patients and laboratories, lack sensitivity and specificity, and rarely alter management in cirrhotics.

Instead, assess for signs and symptoms suggestive of hepatic encephalopathy in patients with chronic liver disease:

• Grade I: sleep reversal/behavior change
• Grade II: lethargy, confusion
• Grade III: stupor, incoherent, arousable
• Grade IV: coma

Importantly, these symptoms in patients without chronic liver disease or portosystemic shunting do not constitute hepatic encephalopathy and require an alternative diagnostic evaluation.

Mistake 2: The “Protein Starvation” Error

Patients with cirrhosis are often malnourished, and protein restrictions are associated with increased mortality, so patients with hepatic encephalopathy should generally not have their protein intake restricted. Patients with mild to moderate hepatic encephalopathy can typically take nutrition orally.

Patients with severe hepatic encephalopathy usually do not receive oral nutrition, but as soon as they improve, a standard diet can be given. Patients should be instructed to eat small meals throughout the day, with a late-night snack of complex carbohydrates, because fasting results in the production of glucose from amino acids, leading to the production of ammonia.

Mistake 3: Missing the “Precipitants” (The Trigger)

This is the single most common reason patients fail to improve despite adequate lactulose. Treatment of precipitating causes combined with pharmacologic therapy is typically associated with prompt improvement in mental status and hepatic encephalopathy.

Here is a high-yield precipitant checklist:

• GI bleeding
• Infection (SBP, UTI, pneumonia, etc.)
• Hypovolemia/dehydration from overdiuresis or other causes.
• Renal failure
• Constipation
• Electrolytes: hypokalemia + metabolic alkalosis
• Hypoxia
• Hypoglycemia
• Sedatives/benzos
• Rare: HCC, portal/hepatic vein thrombosis

Prompt identification and aggressive treatment of precipitating factors is essential; failure to do so delays clinical response.

Mistake 4: Poor Lactulose Titration

The goal of lactulose or other nonabsorbable disaccharides, such as lactitol, is to achieve two to three soft stools per day without diarrhea (Diarrhea can worsen hepatic encephalopathy, as it can lead to dehydration and hypokalemia). So titare up and down to achieve this goal.

Lactulose and lactitol act through a variety of mechanisms that lead to decreased absorption of ammonia from the gastrointestinal tract.

The typical dose of oral lactulose is 30 to 45 mL (20 to 30 grams), two to four times per day. An equivalent dose of lactitol is approximately 30 to 60 grams (powder), diluted according to the label (eg, in 100 mL of water), given orally in two to four divided doses per day.

Lactulose enemas can be given if the patient cannot take it orally. We mix 300 ml of lactulose with 700 ml of tap water or saline given as a 30-60-minute retention enema every 4-8 hours/day until the patient can take PO. Rectal tube isn’t required to administer lactulose enema, as it may cause discomfort, rectal irritation, and potential injury to the rectal mucosa.

In cases of severe leakage in patients with severe fecal incontinence or inability to retain the enema solution, or in cases where prolonged retention of the enema solution is necessary, a rectal tube can be used.

We do not administer therapy by nasogastric tube because of the risk of aspiration.

Mistake 5: The “Wait and See” with Rifaximin

Rifaximin was approved as an add-on therapy to lactulose for secondary prophylaxis of overt HE. It is never a standalone treatment. In Acute HE, it isn’t a first-line treatment but should be added if there is no clinical improvement within 48 hours of treatment with lactulose or lactitol. If the patient is already on rifaximine at home, we must continue that.

The standard dose of rifaximine is 550 mg PO BID.

Bonus

Lactulose is recommended as chronic therapy for all patients with cirrhosis who have experienced at least one episode of overt hepatic encephalopathy (OHE) for secondary prophylaxis, and rifaximin should be added if there is recurrence or intolerance to lactulose.