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Randomised controlled trial of lactulose versus rifaximin for prophylaxis of hepatic encephalopathy in patients with acute variceal bleed
  1. Sudhir Maharshi,
  2. Barjesh Chander Sharma,
  3. Siddharth Srivastava,
  4. Amit Jindal
  1. Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
  1. Correspondence to Dr Barjesh Chander Sharma, Department of Gastroenterology, Room No. 203, Academic Block, G.B. Pant Hospital, New Delhi 110002, India; drbcsharma{at}

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We read with interest the article by Peter Ferenci1 on the diagnosis of minimal hepatic encephalopathy (HE), still a challenge, and Goldbecker et al 2 on the comparison of the most favoured methods for the diagnosis of HE in liver transplantation candidates. Identification and treatment of the precipitating factors are the primary therapeutic option for HE. Variceal bleed seen in 25%–30% of patients with cirrhosis is an important precipitating factor for development of HE, and associated with increased morbidity and mortality.3 ,4 Acute variceal bleed (AVB) is an important precipitating factor for development of HE. There is a role of lactulose for prophylaxis of HE after AVB;5 however, there are no data on the role of rifaximin for prophylaxis of HE after AVB. We performed this study to compare the efficacy of lactulose versus rifaximin for prophylaxis of HE after AVB in patients with cirrhosis. Consecutive patients of cirrhosis with AVB and no HE at time of presentation were randomised to lactulose group (Gp-L (30 mL 6 h)) or rifaximin group (Gp-R (400 mg 8 h)) for 5 days along with standard treatment of AVB as per Baveno V guidelines. Primary endpoint was development of overt HE as per West Haven criteria within 5 days of randomisation. Secondary endpoints were any adverse side effects and death. In all, 120 patients were randomised into two groups, Gp-L (n=60, age 41.8±9.5 years, 50 men) and Gp-R (n=60, age 39.2±10.3 years, 51 men). There was no significant difference in baseline demographic, laboratory, arterial ammonia level, child score, model for end stage liver disease (MELD) score and aetiology of cirrhosis in between the two groups. Characteristics of variceal bleed were also similar in Gp-L vs Gp-R (mean arterial pressure 79.3±6.1 vs 82.1±6.9 mm Hg, p=0.34), haemoglobin (77±15 vs 78±13 g/L, p=0.27), time to endoscopy (6.3±1.6 vs 6.1±1.7 h, p=0.64), blood unit transfused (1.9±1.0 vs 1.7±1.1 g/L, p=0.46) and oesophageal source of bleed (90% vs 92%, p=0.72) (table 1).

Table 1

Characteristics of bleed at the time of enrolment in two groups

There was no difference in development of HE (Gp-L vs Gp-R 10/60 vs 9/60; p=1.0) and mortality (Gp-L vs Gp-R 8/60 vs 9/60; p=1.0) in the two groups (table 2).

Table 2

Primary and secondary outcomes of the study in two groups

The majority of the patients (52.6%) developed grade 2 HE. The median grade of HE was 2 (range 1–4) and median time interval of development of HE was 2 days (range 1–5) from the time of randomisation. Hospital stay between lactulose and rifaximin group was comparable, but a significant difference was observed in hospital stay for patients with HE and without HE in either group. A total of 16 (26.6%) patients experienced diarrhoea and 9 (15%) had abdominal bloating in Gp-L, while 3 (5%) patients experienced abdominal pain and nausea in rifaximin, but no patient was withdrawn from the trial due to these adverse effects. Baseline MELD score, Child-Turcotte-Pugh score, bilirubin, arterial ammonia, heart rate, mean arterial pressure and total leucocyte count significantly correlated with development of HE. On multivariate analysis, only baseline arterial ammonia and blood transfusion requirement during hospital stay were the predictors of development of HE (table 3).

Table 3

Multivariate analysis for patients who developed hepatic encephalopathy

The results of two recently published meta-analyses which compared the efficacy of oral non-absorbable disaccharides versus rifaximin in the management HE showed that both lactulose and rifaximin are equally effective and rifaximin is better tolerated.6 ,7 In our study, rifaximin was not superior to lactulose for prophylaxis of HE in patients of cirrhosis with AVB and well tolerated. It will be worthwhile to give rifaximin or lactulose as a standard treatment in the management of AVB in patients with cirrhosis to prevent HE considering the prognosis, burden and associated cost in the management of HE.


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  • Contributors SM and AJ: Patient enrolment, study investigations, data recording and analysis, interpretation of data, drafting of manuscript. BCS and SS: Study conception and design, study supervision, critical revision for important intellectual content, final approval of the version to be published. BCS: Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of article are appropriately investigated and resolved.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Institutional Ethics Committee, Maulana Azad Medical College and associated Hospitals, New Delhi, India.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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