Gastroenterology

Gastroenterology

Volume 140, Issue 2, February 2011, Pages 478-487.e1
Gastroenterology

Clinical—Liver, Pancreas, and Biliary Tract
Rifaximin Improves Driving Simulator Performance in a Randomized Trial of Patients With Minimal Hepatic Encephalopathy

https://doi.org/10.1053/j.gastro.2010.08.061Get rights and content

Background & Aims

Patients with cirrhosis and minimal hepatic encephalopathy (MHE) have driving difficulties but the effects of therapy on driving performance is unclear. We evaluated whether performance on a driving simulator improves in patients with MHE after treatment with rifaximin.

Methods

Patients with MHE who were current drivers were randomly assigned to placebo or rifaximin groups and followed up for 8 weeks (n = 42). Patients underwent driving simulation (driving and navigation tasks) at the start (baseline) and end of the study. We evaluated patients' cognitive abilities, quality of life (using the Sickness Impact Profile), serum levels of ammonia, levels of inflammatory cytokines, and model for end-stage-liver disease scores. The primary outcome was the percentage of patients who improved in driving performance, calculated as follows: total driving errors = speeding + illegal turns + collisions.

Results

Over the 8-week study period, patients given rifaximin made significantly greater improvements than those given placebo in avoiding total driving errors (76% vs 31%; P = .013), speeding (81% vs 33%; P = .005), and illegal turns (62% vs 19%; P = .01). Of patients given rifaximin, 91% improved their cognitive performance, compared with 61% of patients given placebo (P = .01); they also made improvements in the psychosocial dimension of the Sickness Impact Profile compared with the placebo group (P = .04). Adherence to the assigned drug averaged 92%. Neither group had changes in ammonia levels or model for end-stage-liver disease scores, but patients in the rifaximin group had increased levels of the anti-inflammatory cytokine interleukin-10.

Conclusions

Patients with MHE significantly improve driving simulator performance after treatment with rifaximin, compared with placebo.

Section snippets

Materials and Methods

The trial was conducted under a Food and Drug Administration investigational new drug number (77783) and was registered at www.clinicaltrials.gov number (NCT00533910) before enrollment was initiated. Enrollment was performed at the Medical College of Wisconsin and at McGuire Veterans Affairs Medical Center.

Results

A total of 203 patients with cirrhosis were considered for this study. The majority, 97 patients, were excluded owing to use of psychoactive drugs (lactulose alone in 45, non-selective serotonin reuptake inhibitors antidepressants in 21, rifaximin in 12, antiseizure medications in 10, and benzodiazepines in 9), 38 were excluded because of normal performance on the cognitive battery, and 26 were excluded because they were not current car drivers. Forty-two patients were ultimately included into

Discussion

The randomized, placebo-controlled, double-blind trial shows that patients randomized to rifaximin have a higher rate of improvement in total driving errors, specifically speeding tickets and navigation of illegal turns on a driving simulator compared with those on placebo. This was accompanied by improved cognitive performance and psychosocial aspects of quality of life in the rifaximin group.

Driving requires balance and integration of different cognitive inputs, most of which are affected

References (48)

  • J.S. Bajaj et al.

    Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy

    Hepatology

    (2009)
  • J.S. Bajaj et al.

    Navigation skill impairment: another dimension of the driving difficulties in minimal hepatic encephalopathy

    Hepatology

    (2008)
  • G. Kircheis et al.

    Hepatic encephalopathy and fitness to drive

    Gastroenterology

    (2009)
  • H. Schomerus et al.

    Latent portasystemic encephalopathy. I. Nature of cerebral functional defects and their effect on fitness to drive

    Dig Dis Sci

    (1981)
  • A. Watanabe et al.

    Evaluation of neuropsychological function in patients with liver cirrhosis with special reference to their driving ability

    Metab Brain Dis

    (1995)
  • J.S. Bajaj et al.

    The effect of fatigue on driving skills in patients with hepatic encephalopathy

    Am J Gastroenterol

    (2009)
  • M. Groeneweg et al.

    Subclinical hepatic encephalopathy impairs daily functioning

    Hepatology

    (1998)
  • J.S. Bajaj et al.

    Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations

    Am J Gastroenterol

    (2007)
  • J.S. Bajaj et al.

    Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test

    Hepatology

    (2009)
  • D. Haussinger et al.

    Pathogenetic mechanisms of hepatic encephalopathy

    Gut

    (2008)
  • D.L. Shawcross et al.

    Role of ammonia and inflammation in minimal hepatic encephalopathy

    Metab Brain Dis

    (2007)
  • R.K. Dhiman et al.

    Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy

    Dig Dis Sci

    (2000)
  • S. Prasad et al.

    Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy

    Hepatology

    (2007)
  • P.S. Kamath

    The need for better clinical trials

    Hepatology

    (2008)
  • Cited by (193)

    • Social Impact of Hepatic Encephalopathy

      2024, Clinics in Liver Disease
    • Minimal Hepatic Encephalopathy

      2024, Clinics in Liver Disease
    • A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study

      2023, Journal of Hepatology
      Citation Excerpt :

      Exploratory with specialized blood work: We also conducted a biochemical analysis on serum samples drawn at baseline, EOD and EOS for % ischemia-modified albumin (IMA), serum lipopolysaccharide-binding protein (LBP), inflammatory cytokines (IL-6, TNF-α, IL-10, IL-1β), and markers of endothelial dysfunction (asymmetric dimethyl arginine [ADMA] and soluble intercellular adhesion molecule [sICAM-1]).8 Sample size: In a prior study of individuals without HE, using rifaximin, there was a 90% improvement in the treatment group compared to 60% with placebo and in another study using fecal transplant in HE, there was again a 90% improvement compared to standard of care.18,19 Since cognitive impairment was significantly worse in our group with prior HE, we expected the placebo arm not to respond as well and therefore, assumed that 70% of the albumin group would improve compared to 30% of the placebo group.

    • The human microbiota and its therapeutic options

      2023, Molecular Medical Microbiology, Third Edition
    View all citing articles on Scopus

    View this article's video abstract at www.gastrojournal.org

    Conflicts of interest The authors disclose the following: Jasmohan Bajaj has received funding and has been on advisory boards and a consultant for Salix Pharmaceuticals and Ocera Therapeutics; Arun Sanyal is a consultant and has been on advisory boards for Salix Pharmaceuticals. The remaining authors disclose no conflicts.

    Funding This study was supported in part by the clinical research center grant MO1-RR00058, national center for research resources (NCRR), National Institutes of Health, and an investigator-initiated grant by Salix Pharmaceuticals (J.S.B.).

    Because this was an investigator-initiated project, Salix provided funding but was not involved in protocol design and implementation, data collection, analysis, or interpretation of the study results.

    View full text