What adjustments can be made to the treatment plan for a patient with hepatic encephalopathy who is already on Rifaxamin (Rifaximin) and experiencing frequent triggers, with infection and other causes ruled out?

Add Lactulose to Rifaximin Immediately

The most critical adjustment is to add lactulose (20-30g orally 3-4 times daily) to the rifaximin regimen, as rifaximin should never be used as monotherapy for hepatic encephalopathy. 1, 2

Why Lactulose Must Be Added

The patient is experiencing treatment failure because rifaximin alone is insufficient. The evidence is unequivocal:

• Combination therapy with rifaximin plus lactulose reduces hepatic encephalopathy recurrence from 45.9% to 22.1% (hazard ratio 0.42), compared to lactulose alone 2, 3
• Over 90% of patients in the landmark rifaximin trial were on concurrent lactulose therapy 3
• Rifaximin monotherapy should only be considered when lactulose is poorly tolerated, and this is based on expert opinion rather than robust evidence 2

Specific Dosing Algorithm

Step 1: Initiate Lactulose Properly

• Start lactulose 20-30g (30-45 mL) orally 3-4 times daily 1, 2
• Titrate to achieve 2-3 soft bowel movements per day - this is the therapeutic target, not an arbitrary dose 1, 2
• If unable to take orally, administer via nasogastric tube 1

Step 2: Optimize Rifaximin Dosing

• Continue rifaximin 550 mg twice daily (or 400 mg three times daily) 1, 2
• The FDA label supports both dosing regimens 4
• Evidence suggests once-daily dosing may be insufficient 5

Step 3: Monitor for Common Pitfalls

• Failing to titrate lactulose to achieve 2-3 bowel movements daily is the most common cause of treatment failure 2
• Patients often under-dose lactulose due to concerns about diarrhea, but the therapeutic effect requires adequate bowel frequency 1

Additional Therapeutic Options if Combination Therapy Fails

If the patient continues to have breakthrough episodes despite optimized rifaximin plus lactulose:

Consider Adding L-ornithine-L-aspartate (LOLA)

• Intravenous LOLA 30g/day can be added to lactulose 1
• Combination of lactulose plus LOLA showed shorter time to symptom recovery (1.92 vs 2.50 days, p=0.002) compared to lactulose alone 1

Consider Branched-Chain Amino Acids (BCAAs)

• Oral BCAAs at 0.25 g/kg/day can be added 1
• BCAAs inhibit proteolysis and decrease influx of toxic materials via the blood-brain barrier 1

Consider Albumin Therapy

• Albumin 1.5 g/kg/day until clinical improvement or for 10 days maximum 1

When to Refer for Liver Transplantation

Recurrent or persistent hepatic encephalopathy despite adequate medical treatment (lactulose plus rifaximin) should prompt evaluation for liver transplantation 2

• A first episode of overt hepatic encephalopathy should already have prompted referral to a transplant center 2
• This patient with recurrent episodes despite rifaximin is a transplant candidate 2

Evidence Supporting This Approach

The combination therapy approach is supported by the highest quality evidence:

• Combination therapy showed better recovery within 10 days (76% vs 44%, p=0.004) and shorter hospital stays (5.8 vs 8.2 days, p=0.001) compared to lactulose alone 1
• Meta-analysis of 19 RCTs showed rifaximin reduced mortality (RR 0.50) and increased recovery from hepatic encephalopathy (RR 0.59) 2, 6
• When rifaximin plus lactulose was compared to lactulose alone, there was a reduction in overall mortality risk (RR 0.69,95% CI 0.55-0.86) 7