Hepatic encephalopathy (HE) has a large impact on the patient, caregivers, and health care team. From 2005 to 2009, there were 110,000 hospitalized patients in the United States. Overt hepatic encephalopathy (OHE) may occur in up to 50[percent] of all cirrhotic patients. In 2013, the American Association for the Study of Liver Diseases (AASLD) in conjunction with the European Association for the Study of the Liver (EASL) released a treatment guideline for the management of hepatic encephalopathy. In addition to developing the definition and classification, treatment approaches were developed with a caveat that the evidence supporting treatment was not the most robust. This review is of the recommendations from the guidelines, as well as a review of specific literature

Ausmus, Ashley

Ludwig, Shannon

University of Missouri: MOspace

5/30/2018 Overt Hepatic Encephalopathy: Pharmacotherapy Reviewhttps://www.printfriendly.com/p/g/rY6Azf 1/6January 5, 2015Overt Hepatic Encephalopathy: Pharmacotherapy Reviewmedicine2.missouri.edu/jahm/overt-hepatic-encephalopathy-pharmacotherapy-review/Ashley Ausmus, PharmD Shannon Ludwig PharmD, BCPSDepartment of Pharmacy, Internal Medicine, University of Missouri Health Care, Columbia, MOAddress for Correspondence: ausmusash@health.missouri.eduCitation: A Ausmus, S Ludwing. Overt Hepatic Encephalopathy: Pharmacotherapy Review. Journal ofAcademic Hospital Medicine 2015, Volume 7, Issue 1INTRODUCTIONHepatic encephalopathy (HE) has a large impact on the patient, caregivers, and health care team. From 2005 to 2009, there were 110,000 hospitalized patients in the United States.  Overt hepaticencephalopathy (OHE) may occur in up to 50% of all cirrhotic patients.  In 2013, the AmericanAssociation for the Study of Liver Diseases (AASLD) in conjunction with the European Associationfor the Study of the Liver (EASL) released a treatment guideline for the management of hepaticencephalopathy.  In addition to developing the definition and classification, treatment approacheswere developed with a caveat that the evidence supporting treatment was not the most robust.This review is of the recommendations from the guidelines, as well as a review of specific literature.AASLD/EASL hepatic encephalopathy utilized the following score for determining the level ofevidence behind each recommendation (table 1).Table 1. GRADE system for evidenceGrade EvidenceI Randomized, control trialsII-1 Controlled trials, without randomizationII-2 Cohort or case-control studiesII-3 Multiple time series, uncontrolled experimentsIII Expert opinion or descriptive epidemiologyEvidence DescriptionHighqualityFurther evidence unlikely to change the estimated effect AModerate Further research is likely to have important impact on our confidence in the estimation ofeffect and may change the estimateB1 , 21,2 1215/30/2018 Overt Hepatic Encephalopathy: Pharmacotherapy Reviewhttps://www.printfriendly.com/p/g/rY6Azf 2/6LowqualityFurther research is likely to have important impact on our confidence in the estimation ofeffect and is likely to change the estimateCRecommendationStrong Factors influencing the quality of the recommendation include quality evidence, patientimportant factors, and costs1Weak More uncertainity, variance in preference or values.  Recommendation with less certainity,higher costs, or resource consumption.2HE has been defined as the brain dysfunction in patients with liver failure with or withoutportosystemic shunting that results in neurological or psychological abnormalities.  Initiation oftherapy for the treatment of HE should begin, but identifying and treating the underlyingprecipitating factor is paramount to successful treatment.  Therapies for treatment of hepaticencephalopathy include nonabsorbable disaccharides (lactulose), rifaxamin, and other treatments.Nonabsorbable DisaccharidesAASLD recommends that the first line of therapy is lactulose (GRADE II-1, B, 1) and lactulose use forprevention of recurrent episodes (GRADE II-1, A, 1).   Lactulose produces reduction of ammonialevels through acidification of the colon which results in conversion of ammonia to ammoniumwhich elicits a prebiotic effect.  In addition lactulose, lactitol, and polytethylene glycol (PEG) producea cathartic effect.  While the evidence supporting the use of lactulose is limited by themethodological deficiencies, the decades of use and cost comparison have led to continuedrecommendation of use.Lactulose vs. PEG-3350A recent article published in JAMA by Rahimi et al studied the use of PEG-3350 solution versuslactulose in hepatic encephalopathy. It was hypothesized that catharsis of the gut would lead torelief in OHE, which would make PEG-3350 superior to lactulose. Primary endpoint was decrease inhepatic encephalopathy scoring algorithm (HESA) score from baseline (table 2).Table 2. HESA Scoring SystemCriteria for ScoringGrade 4 Must include each of the following:No eyes openingNo reaction to simple commandsNo verbal response2115/30/2018 Overt Hepatic Encephalopathy: Pharmacotherapy Reviewhttps://www.printfriendly.com/p/g/rY6Azf 3/6Grade 3 3 or more of the following:SomnolenceConfusionDisorientated to placeBizarre behavior/anger/rageClonus/rigidity/nystagmus/BabinskyNo mental control*Grade 2 Any 3 of the following:LethargyHyperactive reflexesLoss of timeInappropriate behaviorSlurred speechOr any 2 of the following:Slow responses*Anxiety*Amnesia*Impaired simple computation*Grade 1 Any 4 of the following:Sleep disorder/impaired sleepTremorImpaired complex computations*Short attention span*Impaired construction ability*Euphoria or depression*Grade 0 Does not meet any other grade criteria*Symptoms assessed using neuropsychological measuresThe study observed the use of either lactulose or PEG-3350 4-Liters in 50 patients. The authorsfound that PEG-3350 was superior to reducing HESA scores over 24 hours. In the lactulose arm, 52%of patients reached the primary endpoint compared to 91% of patients in the PEG-3350 group (p <0.01). Additionally, the mean (± SD) HESA score change was greater with PEG-3350 treatment (1.5 ±0.8) versus lactulose (1.5 ± 0.8) (p < 0.002), and median time to resolution of HE was shorter withPEG-3350 (p = 0.01). Side-effects were comparable between groups with diarrhea being moreprevalent in the PEG-3350 arm and bloating being more common in lactulose. Electrolyteabnormalities and dehydration were no significantly different between treatment arms, althoughthe study may have been underpowered to detect this.There were many limitations to this study. First, there was limited blinding as it was impossible toblind the PEG-3350 container. Additionally, it was a small, single-centered study. Even though thestudy technically met power, the effect to lactulose may have been underestimated and a largeeffect size for PEG-3350 was assumed. Regardless of these limitations, a large effect was observedand PEG-3350 is as widely available and affordable as lactulose. Further studies on the use of PEG-3350 for HE may be warranted.Rifaximin35/30/2018 Overt Hepatic Encephalopathy: Pharmacotherapy Reviewhttps://www.printfriendly.com/p/g/rY6Azf 4/6The intestinal production of ammonia and its absorption is reduced due to the alteration in thegastrointestinal microflora from the administration of rifaximin.  An additional benefit is the lack ofsystemic side effects seen as rifaximin is not absorbed.  The AASLD guidelines recommend rifaximinas an effective additional therapy for patient on lactulose to prevent the recurrence of episodes(GRADE I, A, 1).Lactulose vs. RifaximinThe controversy of using rifaximin either in place of or in addition to lactulose has waged ondespite current practice guidelines that recommend lactulose as first-line treatment. Rifaximinproved effective compared to placebo in 299 patients with recurrent encephalopathy (HE) who werein remission. Rifaximin 550 mg twice daily did recue the risk of an episode of hepaticencephalopathy (HR 0.42; 95% CI [0.250-0.64]) as well as the risk of hospitalization from hepaticencephalopathy (HR 0.50; 95% CI [0.29 – 0.87]). Of note, over 90% of patients in each arm were onbaseline lactulose and upon sub-group analysis, those patients who were not using lactulose atbaseline had no significant differences in outcomes with rifaximin compared to placebo. Overall,treatment was well tolerated and rifaximin had positive outcomes.In one study by Leevy and Phillips, investigators sought to compare frequency and duration ofhospitalizations related to hepatic encephalopathy with rifaximin versus lactulose. Charts of 145patients using lactulose 30mLs twice daily for ≥ 6 months or rifaximin 400mg three times daily for ≥6 months were retrospectively reviewed. Less patients taking rifaximin were hospitalized during thetreatment period versus those taking lactulose, had shorter hospitalization time, and lowerhospitalization charges (p < 0.001 for all measures). Diarrhea, flatulence, and abdominal pain werereported more in the lactulose group over rifaximin (p < 0.001). Of note, a low compliance rate(defined as missing < 25% of doses) was noted in a large percentage of lactulose patients (31%)versus rifaximin patients (92%) and was attributed to poor tolerability. Another limitation would bethe dosing strategies used. Many patients may require higher doses of lactulose (titrated to 3 to 4loose stools per day) than twice daily. Additionally, recommended dosing for rifaximin in hepaticencephalopathy ranges and is often 550mg twice daily instead of 400mg three times daily.Probably the most common prescribing method is the use of rifaximin with lactulose. A study bySharma et al demonstrated this by comparing lactulose alone to lactulose plus rifaximin. This studyevaluated 120 patients with overt HE (>80% grade 3 or 4) who were randomized to receive eitherlactulose alone or lactulose plus rifaximin. Baseline Child-Pugh was mainly Class B and C and MeanMELD was 24.5 ± 4.2. Of these patients, 55 had experienced previous episodes of HE requiringtreatment, but no patients were refractory to treatments. There were more patients in thecombination therapy group that experienced reversal of HE symptoms within a 10 day period (76%vs. 44% lactulose alone; p = 0.004). Patients treated with both lactulose and rifaximin alsoexperience shorter hospital stays (p = 0.01) and a decrease in mortality (p < 0.05; ARR 25.1%) with anumber needed to treat of 4. There were no notable differences in patients who died due togastrointestinal bleed or hepatorenal syndrome, but there were more deaths due to sepsis inpatients treated with lactulose alone. There were no serious side effects related to either treatmentarm reported with respect to abdominal pain or diarrhea. The authors hypothesized the differentmechanisms of action on gut flora resulted in synergistic action and increased efficacy of the twotreatments together.14565/30/2018 Overt Hepatic Encephalopathy: Pharmacotherapy Reviewhttps://www.printfriendly.com/p/g/rY6Azf 5/6Other studies have shown rifaximin is as effective and possibly superior than conventional therapiessuch as lactulose and is well tolerated. However, there is still a lack of evidence to support rifaximinas sole therapy for HE and the cost of rifaximin greatly exceeds the cost of lactulose. With theavailable data and the updated guidelines from the AASLD, the recommendation is still lactulose asfirst choice for the treatment of HE or for prevention of recurrent HE episodes after initial episodeand rifaximin as effective add-on therapy.Other therapiesThe guidelines currently address other therapies available for use including branch-chained aminoacids (BCAAs), L-ornithine L-aspartate (LOLA), Probiotics, Glutaminase inhibitors, neomycin,metronidazole, albumin, or laxatives. The guidelines conclude BCAA’s, LOLA, neomycin, andmetronidazole may have a role for refractory patients who fail to respond to conventional therapy.Other therapies lack evidence that show benefit and should not be recommended at this time.(AASLD)Summary and RecommendationsOvert hepatic encephalopathy remains a significant complication of cirrhosis. The updated AASLDguidelines highlight the need for better controlled clinical treatments for effects of different formsof HE and specific complications. There is also a lack of standardization between trials which makescomparing treatments difficult. Future studies need to better assess effects of HE on individual andsocietal costs, diagnostic tools, and therapeutic goals.References:1. Vilstrup H, Amodio P, Bajaj J, Cordoba, et al. Hepatic Encephalopathy in Chronic LiverDisease: 2013 Practice Guideline by the American Association for the Study of LiverDiseases and the American Association for the Study of Liver Disease and the EuropeanAssociation for the Study of Liver. Hepatology; 2014: doi:10.1002/hep.27210.2. Leise MD, Poterucha JJ, Kamath PS, Kim WR. Management of Hepatic Encephalopathyin the Hospital. Mayo Clin Proc. 2014;89(2):241-253.3. Rahimi RS, Singal AG, Cuthbert J, Rockey DC. Lactulose vs Polyethylene Glycol 3350 –Electrolyte Solution for the Treatment of Overt Hepatic Encephalopathy (HELP). JAMAIntern Med. 2014; E2 – E7: doi:10.1001/jamainternmed.2013.4746.4. Bass N, Mullen KD, Sanyal A, Poordad F, et al. Rifaximin Treatment in HepaticEncephalopathy. New Eng J Med. 2010; 362: 1071-815. Leevy C, Phillips J. Hospitalizations during the Use of Rifaximin Versus Lactulose for theTreatment of Hepatic Encephalopathy. Dig Dis Sci. 2007; 52: 737-41.6. Sharma BC, Sharma P, Lunia MK, Srivastava S, et al. A Randomized, Double-Blind,Controlled Trial Comparing Rifaximin Plus Lactulose with Lactulose Alone in Treatmentof Overt Hepatic Encephalopathy. Am J Gastro. 2013; 108: 1458- 63.7. Gloud LL, Dam G, Borre M, Les I, et al. Lactulose, rifaximin, or branched chain aminoacids for hepatic encephalopathy: what is the evidence? Metab Brain Dis. 2013; 28: 221-25.8. Eltawil KM, Laryea M, Peltekian K, Molinari M. Rifaximin vs conventional oral therapy forhepatic encephalopathy: a meta-analysis. World J Gastroenterol. 2012; 18(8): 767-77.1,7,85/30/2018 Overt Hepatic Encephalopathy: Pharmacotherapy Reviewhttps://www.printfriendly.com/p/g/rY6Azf 6/6Copyright © 2018 - The Curators of the University of Missouri System. All rights reserved. DMCA and other copyright information. An equal opportunity/affirmative actioninstitution.

Overt hepatic encephalopathy : Pharmacotherapy review

https://mospace.umsystem.edu/xmlui/bitstream/10355/63913/1/JournalOfAcademicHospitalMedicineV7I1Ausmus.pdf

Overt hepatic encephalopathy : Pharmacotherapy review

Abstract

Similar works

Full text

Available Versions

University of Missouri: MOspace