Treating Overt Hepatic Encephalopathy
Objectives: Hepatic encephalopathy (HE) is associated with poor prognosis in cirrhosis. Drugs used in the treatment of HE are primarily directed at the reduction of the blood ammonia levels. Rifaximin and lactulose have shown to be effective in HE. We evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE.
Methods: In this prospective double-blind randomized controlled trial, 120 patients with overt HE were randomized into two groups: (group A lactulose plus rifaximin 1,200 mg/day; n=63) and group B (lactulose (n=57) plus placebo). The primary end point was complete reversal of HE and the secondary end points were mortality and hospital stay.
Results: A total of 120 patients (mean age 39.4±9.6 years; male/female ratio 89:31) were included in the study. 37 (30.8%) patients were in Child–Turcotte–Pugh (CTP) class B and 83 (69.2%) were in CTP class C. Mean CTP score was 9.7±2.8 and the MELD (model for end-stage liver disease) score was 24.6±4.2. At the time of admission, 22 patients (18.3%) had grade 2, 40 (33.3%) had grade 3, and 58 (48.3%) had grade 4 HE. Of the patients, 48 (76%) in group A compared with 29 (50.8%) in group B had complete reversal of HE (P<0.004). There was a significant decrease in mortality after treatment with lactulose plus rifaximin vs. lactulose and placebo (23.8% vs. 49.1%, P<0.05). There were significantly more deaths in group B because of sepsis (group A vs. group B: 7:17, P=0.01), whereas there were no differences because of gastrointestinal bleed (group A vs. group B: 4:4, P=nonsignificant (NS)) and hepatorenal syndrome (group A vs. group B: 4:7, P=NS). Patients in the lactulose plus rifaximin group had shorter hospital stay (5.8±3.4 vs. 8.2±4.6 days, P=0.001).
Conclusion: Combination of lactulose plus rifaximin is more effective than lactulose alone in the treatment of overt HE.
Hepatic encephalopathy (HE) is a serious but potentially reversible disorder with a wide spectrum of neuropsychiatric abnormalities and motor disturbances that range from mild alteration of cognitive and motor function to coma and death. It is a challenging complication of advanced liver disease and is estimated to occur in 30 to 45% of patients with liver cirrhosis and in 10–50% of patients with transjugular intrahepatic portosystemic shunts. Bustamante et al. reported the survival probability of 42% at 1 year of follow-up and 23% at 3 years in patients with cirrhosis with a first episode of acute HE. The primary treatment of HE is the identification and treatment of the precipitating factors. The majority of the drugs used in the treatment of HE are primarily directed at the reduction or elimination of the increased neurotoxic ammonia levels. Lactulose, a nonabsorbable disaccharide, remains the mainstay treatment for HE. Despite the widespread use of lactulose, evidence supporting its efficacy for the treatment of HE is limited. A systematic review of the literature found lactulose to be more effective than placebo in improving HE, but with no effect on mortality. However, when only the highest quality studies were included, no significant effect on improvement of HE was seen with lactulose therapy.
Rifaximin, a semisynthetic derivative of rifamycin, is minimally absorbed. It has broad-spectrum in vitro activity against Gram-positive and Gram-negative aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance. No dosage adjustments are necessary in patients with liver dysfunction or renal insufficiency. With minimal systemic bioavailability, rifaximin may be more conducive to long-term use than other, more bioavailable antibiotics with detrimental side effects. It has been proven to prevent the episode of HE and decrease the risk of hospitalization. In randomized studies, rifaximin was more effective than nonabsorbable disaccharides and had efficacy that was equivalent to or greater than that of other antibiotics used in the treatment of acute HE. In their recent meta-analysis, Eltawil et al. reported that rifaximin is as effective as other conventional oral agents for the treatment of HE with a better safety profile. There is a paucity of data on the evaluation of a combination of rifaximin plus lactulose in the treatment of HE. In this study, we evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE.
Abstract and Introduction
Abstract
Objectives: Hepatic encephalopathy (HE) is associated with poor prognosis in cirrhosis. Drugs used in the treatment of HE are primarily directed at the reduction of the blood ammonia levels. Rifaximin and lactulose have shown to be effective in HE. We evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE.
Methods: In this prospective double-blind randomized controlled trial, 120 patients with overt HE were randomized into two groups: (group A lactulose plus rifaximin 1,200 mg/day; n=63) and group B (lactulose (n=57) plus placebo). The primary end point was complete reversal of HE and the secondary end points were mortality and hospital stay.
Results: A total of 120 patients (mean age 39.4±9.6 years; male/female ratio 89:31) were included in the study. 37 (30.8%) patients were in Child–Turcotte–Pugh (CTP) class B and 83 (69.2%) were in CTP class C. Mean CTP score was 9.7±2.8 and the MELD (model for end-stage liver disease) score was 24.6±4.2. At the time of admission, 22 patients (18.3%) had grade 2, 40 (33.3%) had grade 3, and 58 (48.3%) had grade 4 HE. Of the patients, 48 (76%) in group A compared with 29 (50.8%) in group B had complete reversal of HE (P<0.004). There was a significant decrease in mortality after treatment with lactulose plus rifaximin vs. lactulose and placebo (23.8% vs. 49.1%, P<0.05). There were significantly more deaths in group B because of sepsis (group A vs. group B: 7:17, P=0.01), whereas there were no differences because of gastrointestinal bleed (group A vs. group B: 4:4, P=nonsignificant (NS)) and hepatorenal syndrome (group A vs. group B: 4:7, P=NS). Patients in the lactulose plus rifaximin group had shorter hospital stay (5.8±3.4 vs. 8.2±4.6 days, P=0.001).
Conclusion: Combination of lactulose plus rifaximin is more effective than lactulose alone in the treatment of overt HE.
Introduction
Hepatic encephalopathy (HE) is a serious but potentially reversible disorder with a wide spectrum of neuropsychiatric abnormalities and motor disturbances that range from mild alteration of cognitive and motor function to coma and death. It is a challenging complication of advanced liver disease and is estimated to occur in 30 to 45% of patients with liver cirrhosis and in 10–50% of patients with transjugular intrahepatic portosystemic shunts. Bustamante et al. reported the survival probability of 42% at 1 year of follow-up and 23% at 3 years in patients with cirrhosis with a first episode of acute HE. The primary treatment of HE is the identification and treatment of the precipitating factors. The majority of the drugs used in the treatment of HE are primarily directed at the reduction or elimination of the increased neurotoxic ammonia levels. Lactulose, a nonabsorbable disaccharide, remains the mainstay treatment for HE. Despite the widespread use of lactulose, evidence supporting its efficacy for the treatment of HE is limited. A systematic review of the literature found lactulose to be more effective than placebo in improving HE, but with no effect on mortality. However, when only the highest quality studies were included, no significant effect on improvement of HE was seen with lactulose therapy.
Rifaximin, a semisynthetic derivative of rifamycin, is minimally absorbed. It has broad-spectrum in vitro activity against Gram-positive and Gram-negative aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance. No dosage adjustments are necessary in patients with liver dysfunction or renal insufficiency. With minimal systemic bioavailability, rifaximin may be more conducive to long-term use than other, more bioavailable antibiotics with detrimental side effects. It has been proven to prevent the episode of HE and decrease the risk of hospitalization. In randomized studies, rifaximin was more effective than nonabsorbable disaccharides and had efficacy that was equivalent to or greater than that of other antibiotics used in the treatment of acute HE. In their recent meta-analysis, Eltawil et al. reported that rifaximin is as effective as other conventional oral agents for the treatment of HE with a better safety profile. There is a paucity of data on the evaluation of a combination of rifaximin plus lactulose in the treatment of HE. In this study, we evaluated the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for treatment of overt HE.
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