Rifaximin Treatment in Hepatic Encephalopathy

Bass, Nathan M.; Mullen, Kevin D.; Sanyal, Arun J.; Poordad, Fred; Neff, Guy; Leevy, Carroll B.; Sigal, Samuel H.; Sheikh, Muhammad Y.; Beavers, Kimberly L.; Frederick, Richard; Teperman, Lewis; Hillebrand, Donald J.; Huang, Shirley; Merchant, Kunal; Shaw, Audrey L.; Bortey, Enoch; Forbes, William

doi:10.1056/nejmoa0907893

Cited by 1,079 publications

(951 citation statements)

References 39 publications

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“…6,21,22 New nonabsorbable antibiotics specifically designed for SID, such as rifaximin, should be analyzed in this population, mostly because of the promising results of this drug in the prevention of encephalopathy in patients with cirrhosis. 26,27 Finally, preliminary results suggest that nonantibiotic SID strategies, such as the use of probiotics or prebiotics, could be useful in the prevention of EBIs in LTRs. 28 This study has some limitations that deserve specific consideration.…”

Section: Discussionmentioning

confidence: 99%

Selective intestinal decontamination with fluoroquinolones for the prevention of early bacterial infections after liver transplantation

et al. 2011

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The role of selective intestinal decontamination with fluoroquinolones (FQ-SID) in the prevention of early bacterial infections (EBIs) in liver transplant recipients (LTRs) is unknown. We used the online database of the Spanish Network of Infection in Transplantation/ Spanish Network for Research in Infectious Diseases, which prospectively analyzed 1010 LTRs from 12 Spanish hospitals from September 2003 to February 2005. We compared the incidence and etiology of EBIs (30 days after transplantation) in 415 LTRs from 4 centers that used FQ-SID (>7 days) and in 595 LTRs from 8 hospitals that did not use FQ-SID. A multivariate logistic regression analysis (including an adjustment for the transplant center factor) was performed to evaluate the potential protective factor of FQ-SID in the development of EBIs. We reported 266 EBI episodes in 252 LTRs (incidence ¼ 24.9%). There were no differences in the incidence of EBIs between patients in the FQ-SID group and patients not in the FQ-SID group [109/415 (26.3%) versus 143/595 (24%), P ¼ 0.9]. Although LTRs who received FQ-SID had a lower incidence of infections due to enteric bacteria (2.7% versus 6.5%, P ¼ 0.007) and a higher incidence of infections due to nonfermenting gram-negative bacilli (6.6% versus 2.6%, P ¼ 0.004), these findings could not be confirmed after an adjustment by the center factor in the multivariate models. We found no significant differences in the incidence of enterococcal infections (3.4% with FQ-SID versus 3.9% without FQ-SID, P ¼ 0.5). Multivariate analysis did not confirm any protective effect of FQ-SID against the development of EBIs by enteric bacteria. In conclusion, FQ-SID does not reduce the incidence of EBIs in LTRs and could be withheld from this group of patients. Liver Transpl 17:896-904,

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Section: Discussionmentioning

confidence: 99%

Selective intestinal decontamination with fluoroquinolones for the prevention of early bacterial infections after liver transplantation

et al. 2011

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“…A large double-blinded randomized controlled trial of 299 patients, demonstrated an improvement in maintained remission from HE and a reduction in hospitalizations due to HE over a six month period in patients with cirrhosis who were administered rifaximin versus placebo. 120 Increased levels of the antiinflammatory cytokine IL-10 have been found in rifaximin-treated groups which may allude to its mechanism of action being an anti-inflammatory rather than ammonia-lowering in nature. 121 Furthermore, a recent observational study demonstrated that rifaximin-a intriguingly reduced systemic endotoxin levels and disease severity score 122 and may therefore have a therapeutic role in HE by reducing systemic inflammation rather than lowering blood ammonia levels.…”

Section: Rifaximin-amentioning

confidence: 99%

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Aldridge

Tranah

Shawcross

2015

Journal of Clinical and Experimental Hepatology

222

181

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The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. ( J CLIN EXP HEPATOL 2015;5:S7-S20) H epatic encephalopathy (HE) is the term used to encapsulate the broad spectrum of neuropsychiatric disturbances associated with both acute and chronic liver failure (ALF and CLF, respectively), as well as porto-systemic bypass in the absence of hepatocellular disease. The clinical manifestations of HE can be extremely heterogeneous in nature, with symptoms presenting anywhere on a continuum spanning from seemingly normal cognitive performance, right the way through to states of confusion, stupor and coma. In between these extremes, patients with HE may exhibit signs such as inattentiveness, blunted affect, impairment of memory or reversal of the sleep-wake cycle, as well as physical manifestations such as tremor, myoclonus, asterixis and deep tendon hyperreflexia.ALF is defined by the onset of coagulopathy alongside any degree of encephalopathy in patients with no evidence of pre-existing liver disease. 1 The presence of HE in those with ALF is prognostic, with up to a quarter of cases developing raised intracranial pressure. 2 Patients presenting with ALF are at risk of developing its cardinal, lifethreatening feature, cerebral edema. Left untreated, cerebral edema can rapidly progress to cause herniation of the uncus through the falx cerebri, leading to compression of the brainstem and, ultimately, death. H...

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“…47,49 Sharma et al 47 showed in 125 cirrhotic patients who had recovered from at least one previous episode of HE that significantly more patients in the placebo group (30 of 64 patients [46.8%]) than in the lactulose group (12 of 61 patients [19.6%]) developed HE (P = 0.001). Bass and colleagues 49 enrolled 299 cirrhotic patients with a history of at least two episodes of overt HE to receive either rifaximin (550 mg twice daily; n = 140) or placebo (n = 159) for a period of 6 months. More than 90% of patients in both groups were also maintained on concomitant lactulose therapy.…”

Section: Secondary Prophylaxis Of Hepatic Encephalopathymentioning

confidence: 99%

Management of Overt Hepatic Encephalopathy

Sharma

2015

Journal of Clinical and Experimental Hepatology

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Hepatic encephalopathy (HE) is an important complication of cirrhosis with significant morbidity and mortality. Management of HE primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as non-absorbable disaccharides, antimicrobial agents like rifaximin and L-ornithine L-aspartate. The non-absorbable disaccharides which include lactulose and lactitol are considered the first-line therapy for the treatment of HE and in primary and secondary prophylaxis of HE. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Rifaximin is effective in treatment of HE and recent systemic reviews found it comparable to disaccharides and is effective in secondary prophylaxis of HE. H epatic encephalopathy (HE) is a complex neuropsychiatric syndrome, which may complicate acute, chronic liver failure or patients with portal-systemic shunting. It is characterized by changes in mental state including a wide range of neuropsychiatric symptoms ranging from minor signs of altered brain function to deep coma. 1,2 It is one of the commonest indications for admission in intensive care unit in patients with advanced cirrhosis. There were over 40 000 patients hospitalized in the United States alone for a primary diagnosis of HE, resulting in total charges of approximately $932 million. Data in other countries are lacking, hence it causes a huge burden financially to the patient and society. 3 The West Haven Criteria are most often used to grade HE, with scores ranging from I-IV (IV being coma). However, it is a challenge to diagnose patients with minimal hepatic encephalopathy (MHE) or grade 1 HE; so it might be practical to combine these entities and name them covert HE for clinical use and overt HE to patients with grade II to IV. 1,4,5 One of the major tenets of the pathophysiology of HE is hyperammonemia that results from an increased nitrogenous load from the gastrointestinal tract and reduced urea synthesis both due to portal-systemic shunting and decreased urea hepatic synthesis. Brain and skeletal muscle neither remove nor produce ammonium in normal conditions, but they are able to seize ammonium during hyperammonemia, releasing glutamine. Ammonia is produced both by bacterial degradation of amines, aminoacids, purines, and urea as well as enterocytic glutaminase activity that converts glutamine to glutamate and ammonia. 6,7 Astrocytes play an important role in the pathogenesis of HE with consequences for neuronal function. Astrocytes have the ability to eliminate ammonia by the synthesis of glutamine through amidation of glutamate by the enzyme glutamine synthetase Hyperammonemia leads to the accumulation of glutamine within astrocytes, which exerts an osmotic stress that causes astrocytes to take in water and swell. 8,9 This article reviewed the clinical impact, pathogenesis, and management of overt HE in patients with cirrhosis. Articles published between January 1960 and November 2013 were acquired through a MEDLINE search of different combi...

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Rifaximin Treatment in Hepatic Encephalopathy

Abstract: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

Cited by 1,079 publications

References 39 publications

Selective intestinal decontamination with fluoroquinolones for the prevention of early bacterial infections after liver transplantation

Selective intestinal decontamination with fluoroquinolones for the prevention of early bacterial infections after liver transplantation

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Management of Overt Hepatic Encephalopathy

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