Skip to main content
NCBI home page
The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2017 Jul 25;2017(7):CD006314. doi: 10.1002/14651858.CD006314.pub2

Antibiotics for hepatic encephalopathy

Maicon Falavigna 1,✉, Christian Kieling 2, Fernando H Wolff 1, Lídia RF Medeiros 3, Hugo Cheinquer 4
PMCID: PMC6483134

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the beneficial and harmful effects of antibiotics in patients with hepatic encephalopathy and to compare antibiotics with other drugs. Furthermore, we aim at examining whether the beneficial and harmful effects of different antibiotics regimens are equivalent or not.

Background

Hepatic encephalopathy, or portosystemic encephalopathy, represents a reversible decrease in neurologic function caused by hepatic insufficiency. The onset is usually insidious and characterized by subtle and sometimes intermittent changes in memory, personality, concentration, level of consciousness, motor function, and reaction time (Fitz 2002; Schiano 2002).

The pathophysiology of hepatic encephalopathy is still uncertain, but the prevailing assumption is that different toxins, such as false neurotransmitters, natural benzodiazepines, short chain fatty acids, and mercaptans enhance the negative effects of ammonia on the level of consciousness (James 1979; Butterworth 2002). Ammonia has historically been seen as the most important factor in the genesis of hepatic encephalopathy and is still considered one of the most important toxins responsible for this syndrome (Mullen 1999; Fitz 2002; Schiano 2002). In most clinical series, elevated blood ammonia levels are detected in 60% to 80% of patients with cirrhosis and encephalopathy, and therapy targeting the reduction of ammonia concentration often results in resolution of clinical features (Conn 1977; Bucci 1993; Rodes 1993).

Classic hepatic encephalopathy treatment includes intensive supportive care, identification and correction of the precipitating causes, dietary restrictions, and use of nonabsorbable disaccharides and/or oral antibiotics (Fitz 2002; Schiano 2002). Along with correction of underlying causes, treatment of hepatic encephalopathy attempts to lower ammonia circulating levels. Such therapies comprise removal of the ammonia source from the intestinal tract, trapping ammonia in the colon to prevent its systemic absorption, and, in some patients, providing specific therapy to decrease the number of ammonia‐producing bacteria in the colon.

Nonabsorbable disaccharides represent the mainstays of medical therapy for hepatic encephalopathy. These agents target the production and absorption of ammonia and benzodiazepine receptor ligands in the gut. However, the use of lactulose/lactiol is not based on high‐quality evidence, and a recent Cochrane systematic review (Als‐Nielsen 2006a) questions its beneficial effects and use as standard therapy in trials evaluating other treatments for hepatic encephalopathy. Dopaminergic agonists (Als‐Nielsen 2006b) and branched‐chain amino acids (Als‐Nielsen 2006c) have not proved to be significantly effective in the treatment of hepatic encephalopathy. Conclusions of both reviews were constrained by the small number of patients studied and by the limited methodological quality of the included trials. Benzodiazepine receptor antagonists were also studied in a Cochrane review. Results showed positive effect on short‐term improvement, without significant effects on recovery or survival (Als‐Nielsen 2006d). The authors considered it necessary to assess if the use of flumazenil leads to a sustained improvement or increased survival before its inclusion in clinical practice.

Several oral antibiotics, including neomycin, metronidazole, and rifaximin, are effective in lowering blood ammonia levels and are also used in the management of hepatic encephalopathy (Alexander 1992; Zeneroli 2005). Neomycin, a poorly absorbed aminoglycoside antibiotic, has shown similar efficacy to lactulose in the treatment of hepatic encephalopathy (Conn 1977), but the occurrence of side effects (ototoxicity and/or nephrotoxicity) has limited its use (Bosch 1994; Mullen 1999). Rifaximin, a non‐absorbable rifamycin‐derivate, is almost unabsorbed by the gut (Descombe 1994), thereby allowing the antibiotic to reach high concentrations in the intestinal tract and to remain in the faeces in its active form (Descombe 1994). Studies suggest that rifaximin decreases ammonia plasma levels and improves the symptoms related to hepatic encephalopathy in cirrhotics (Mas 2003). Unfortunately, most trials were non‐controlled and/or included a relatively low number of patients (Testa 1985; Di Piazza 1991; Williams 2000). In most patients, the response to antibiotics is equivalent to that for lactulose (Conn 1977; Bucci 1993).

We have been unable to identify meta‐analyses or systematic reviews on antibiotics for hepatic encephalopathy apart from the Cochrane review by Als‐Nielsen et al (Als‐Nielsen 2006a). They found that antibiotics seemed significantly more effective than non‐absorbable disaccharides for hepatic encephalopathy. Therefore, we will conduct the present systematic review.

Objectives

To assess the beneficial and harmful effects of antibiotics in patients with hepatic encephalopathy and to compare antibiotics with other drugs. Furthermore, we aim at examining whether the beneficial and harmful effects of different antibiotics regimens are equivalent or not.

Methods

Criteria for considering studies for this review

Types of studies

Inclusion criteria We will include randomised clinical trials irrespective of language, publication status, or blinding. From cross‐over trials, we will include only data from the first period.

Exclusion criteria We will exclude observational and quasi‐randomised studies.

Types of participants

All patients with any grade of acute or chronic hepatic encephalopathy in connection with acute and chronic liver disease as well as fulminant hepatic failure will be included, no matter the etiology of liver disease or factors precipitating the hepatic encephalopathy.

Types of interventions

  • Antibiotics versus placebo or no intervention.

  • Antibiotics versus nonabsorbable disaccharides.

  • Antibiotics versus other interventions with potential effects on hepatic encephalopathy (ie, benzodiazepine receptor antagonists). This comparison is also included in the review by Als‐Nielsen et al (Als‐Nielsen 2006a), but we will update the analysis with any new trials or data.

  • One antibiotic versus another antibiotic.

Trials will be included regardless of dose, duration, mode of administration, or formulation of interventions. Co‐interventions will be permitted if received by both arms of the trial.

Types of outcome measures

Primary outcome measures

  • Mortality at the maximum follow‐up of individual trials.

  • Number of patients without improvement of hepatic encephalopathy using the definitions of individual trials at maximum follow‐up.

Secondary outcome measures

  • Number of patients without improvement of hepatic encephalopathy using the definitions of individual trials at the end of treatment.

  • Number of patients without recovery from hepatic encephalopathy at maximum follow‐up and at the end of treatment. Recovery is defined as a complete resolution of clinical symptoms of hepatic encephalopathy.

  • Time to recovery, ie, the number of days with hepatic encephalopathy from the time of randomisation to complete recovery.

  • Treatment discontinuation.

  • Number and type of adverse events. Adverse events will be graded as serious and non‐serious according to the International Conference on Harmonisation Guidelines (ICH‐GCP 1997).

  • Quality of life.

  • Cost‐effectiveness.

  • Plasma ammonia concentrations.

Search methods for identification of studies

We will search The Cochrane Hepato‐Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS (Royle 2003), as well as grey literature, using the preliminary search strategies proposed in Appendix 1.

We will identify further trials by reading the reference lists of the identified studies. We will write to the principal investigators of each identified randomised trial and enquire about additional trials they might be aware of.

Data collection and analysis

We will follow the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2005) and the Cochrane Hepato‐Biliary Group Module (Gluud 2006).

Selection of trials All eligible trials will be assessed for their methodological quality and relevance to the review objectives. Two authors (MF, CK) will undertake the trial selection. The authors will be unblinded with regard to the names of the authors, investigators, institutions, and results. The authors will independently extract data to assess whether the trials meet the inclusion criteria. Discrepancies will be resolved by discussion and involvement of a third author (FHW) when necessary. Excluded trials will be identified and listed with the reason for exclusion.

Contact with the authors will be sought if further clarification is necessary.

Data extraction Standardised extraction sheets will be designed and pilot tested before use. The following data will be extracted:

  • Trial characteristics: methodological quality, design, number of intervention arms, number of patients with missing data, and length of follow‐up.

  • Patient characteristics: number of patients randomised to each intervention arm, mean (or median) age, number of males, form and stage of hepatic encephalopathy, mean duration of hepatic encephalopathy at randomisation, type of underlying liver disease, factors precipitating acute hepatic encephalopathy.

  • Intervention characteristics: type and dose of experimental and control intervention, duration of therapy, mode of administration, type and dose of additional interventions.

  • Outcomes: all outcomes will be extracted from each trial.

Methodological quality Methodological quality will be defined as the confidence that the design and report of the randomised trial would restrict bias in the comparison of the intervention (Moher 1998). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001), the methodological quality of trials will be assessed based on the generation of the allocation sequence, allocation concealment, blinding, and follow‐up. These quality components will be classified as follows:

Generation of the allocation sequence

  • Adequate: table of random numbers, computer generated random numbers, or similar.

  • Unclear: the trial was described as randomised, but the generation of the allocation sequence was not described.

  • Inadequate: quasi‐randomised study (which will be excluded).

Allocation concealment

  • Adequate: concealed up to the point of treatment by central randomisation, sealed envelopes, or similar.

  • Unclear: the allocation concealment was not described.

  • Inadequate: open table of random numbers or similar or quasi‐randomised study.

Blinding

  • Adequate: using identical placebo or similar.

  • Unclear: the trial was described as double blind, but the method of blinding was not described.

  • Not performed: tablets versus injections or similar.

Follow‐up

  • Adequate: number and reasons for dropouts and withdrawals were described.

  • Unclear: the report gave the impression that there were no dropouts or withdrawals, but this was not specifically stated.

  • Inadequate: number and reasons for dropouts and withdrawals not described.

Furthermore, we will register whether or not the randomised clinical trials used intention‐to‐treat analysis, blinding assessment of outcome measures, and sample‐size calculation.

Statistical analysis

Statistical analyses will be performed in accordance with the guidelines developed by the Cochrane Collaboration (Higgins 2005). Analyses will include all patients irrespective of follow‐up, according to the intention‐to‐treat principle. If patients have missing outcome data, we will use the last reported observed response ('carried forward') (Hollis 1999).

Statistical heterogeneity among results of different studies will be examined by checking the usual test statistics (Cochrane's Q), with significance set at p < 0.1. Inconsistency test (I²) will be performed (Higgins 2003).

For time‐to‐event outcomes, the hazard ratio (HR) will be used. Where it has not been provided, it will be estimated, if possible, indirectly from other summary statistics (Parmar 1998). Where this is not possible, the relative risks (RR) will be calculated and combined for meta‐analyses with RevMan software (RevMan 2003). Applicability to individual patients will be determined by calculating absolute risk reduction (ARR), number needed to treat (NNT), and number needed to harm (NNH) whenever overall results were statistically significant.

Continuous data will be combined for meta‐analysis. We will use mean and standard deviations to derive a weighted mean difference (WMD).

As a general rule, a fixed‐effect model will be used for calculations of summary estimates and their 95% confidence intervals. If there is heterogeneity, a random‐effects model will also be used (Deeks 2005). Potential sources of heterogeneity will be explored through subgroup analyses with regard to the methodological quality, form and stage of hepatic encephalopathy, and treatment regimens. Test of interaction will be performed to compare differences among estimates of subgroup analyses (Altman 2003). Whenever possible, funnel plot asymmetry will be used to assess the existence of publication bias (Egger 1997).

We will perform subgroup/sensitivity analyses based on the following items:

  • Methodological quality of the trials: comparison of survival and improvement rates in trials with adequate versus inadequate or unclear generation of the allocation sequence, allocation concealment, double blinding, and follow‐up.

  • Co‐interventions: comparison of survival and improvement rates in trials with co‐interventions versus trials without co‐interventions.

  • Etiology of hepatic encephalopathy: comparison of survival and improvement rates in different etiologies of hepatic encephalopathy.

  • Grade of hepatic encephalopathy: comparison of survival, improvement and recovery rates in different grades of hepatic encephalopathy.

  • Publication status: comparison of the survival improvement rates in trials published as abstracts and letters versus full papers.

Acknowledgements

We thank all patients and clinical researchers involved in the publications mentioned in this protocol. We thank Dimitrinka Nikolova for the provided support.

Appendices

Appendix 1. Search Strategies

Database Time span of search Search strategy
The Cochrane Hepato‐Biliary Group Controlled Trials Register The date when the search is performed. (antibiotic* OR 'antibacterial agent*' OR aminoglycosid* OR imidazole* OR rifaximin* OR vancomycin* OR neomycin* OR paromomycin* OR metronidazole*) AND 'hepatic encephalopath*'
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library Latest issue. #1 (antibiotic* OR antibacterial agent* OR aminoglycosid* OR imidazole* OR rifaximin* OR vancomycin* OR neomycin* OR paromomycin* OR metronidazole*) in All Fields in all products #2 MeSH descriptor Anti‐Bacterial Agents explode all trees in MeSH products #3 MeSH descriptor Aminoglycosides explode all trees in MeSH products #4 MeSH descriptor Imidazoles explode all trees in MeSH products #5 MeSH descriptor Vancomycin explode all trees in MeSH products #6 MeSH descriptor Metronidazole explode all trees in MeSH products #7 (#1 OR #2 OR #3 OR #4 OR #5 OR #6) #8 hepatic encephalopathy in All Fields in all products #9 MeSH descriptor Hepatic Encephalopathy explode all trees in MeSH products #10 (#8 OR #9) #11 (#7 AND #10)
MEDLINE (OVID) 1966 to the date the search is performed. #1 Randomized controlled trial pt. #2 Controlled clinical trial.pt. #3 Randomized controlled trials/ #4 random allocation/ #5 double‐blind method/ #6 single‐blind method/ #7 clinical trial.pt. #8 exp clinical trials/ #9 (clin$ adj25 trial$).ti,ab,sh. #10 or/1‐9 #11 singl$ or doubl$ or tripl$ or trebl$).ti,ab,sh. #12 (blind$ or mask$).ti,ab,sh. #13 11 and 12 #14 placebos/ #15 placebo$.ti,ab,sh #16 random$.ti,ab,sh. #17 Research design/ #18 or/14‐17 #19 10 or 13 or 18 #20 animal/ not human/ #21 19 not 20 #22 Anti‐bacterial agents/ #23 exp aminoglycosides/ #24 Vancomycin/ #25 exp imidazoles/ #26 Rifaximin.mp. #27 or/22‐26 #28 Hepatic encephalopathy/ #29 21 and 27 and 28
EMBASE 1980 to the date the search is performed. #1 Controlled study #2 Randomized Controlled trial/ #3 double blind procedure/ #4 single blind procedure/ #5 crossover procedure/ #6 drug comparision/ #7 placebo/ #8 random$.ti,ab,hw,tn,mf. #9 latin square.ti,ab,hw,tn,mf. #10 crossover.ti,ab,hw,tn,mf. #11 cross‐over.ti,ab,hw,tn,mf. #12 placebo$.ti,ab,hw,tn,mf. #13 ((doubl$ or singl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).ti,ab,hw,tn,mf. #14 (comparative adj5 trial$).ti,ab,hw,tn,mf. #15 (clinical adj5 trial$).ti,ab,hw,tn,mf. #16 or/ 1‐15 #17 nonhuman/ #18 animal/ not (human/and animal/) #19 or/17‐18 #20 16 not 19 #21 Anti‐bacterial agents/ #22 exp aminoglycosides/ #23 exp Vancomycin/ #24 exp imidazoles/ #25 exp Rifaximin/ #26 or/21‐25 #27 exp Hepatic encephalopathy/ #28 26 AND 27 #29 20 AND 28
Science Citation Index Expanded (SCI Expanded) (http://portal.isiknowledge.com/portal.cgi?DestApp=WOS&Func=Frame) 1945 to the date the search is performed. #1 TS=(antibiotic* OR 'antibacterial agent*' OR aminoglycosid* OR imidazole* OR rifaximin* OR vancomycin* OR neomycin* OR paromomycin* OR metronidazole*) #2 TS=(hepatic encephalopath*) #3 #2 AND #1 #4 TS=(random* OR blind* OR placebo* OR meta‐analysis) #5 #4 AND #3
LILACS 1980 to the date the search is performed. (antibiot$ or aminog$ or rifaxim$ or imidaz$ or metron$ or neom$ or paramom$ or vancom$) AND (hepatic encephalopathy or encefalopatia hepatica)
Open in a new tab

What's new

Date Event Description
25 July 2017 Amended This withdrawn protocol is replaced by a new protocol for systematic review: Jeyaraj R, Morgan MY, Gluud LL. Aminoglycosides and metronidazole for people with cirrhosis and hepatic encephalopathy (Protocol). Cochrane Database of Systematic Reviews 2017, Issue 7. Art. No.: CD012734. DOI: 10.1002/14651858.CD012734.
Open in a new tab

Contributions of authors

MF ‐ wrote the protocol, except for the Background section. CK ‐ reviewed the protocol. FHW ‐ wrote the Background section of the protocol and reviewed the protocol. LRM ‐ reviewed the protocol and provided technical support in epidemiology. HC ‐ reviewed the protocol and provided technical support in gastroenterology.

Sources of support

Internal sources

  • Universidade Federal do Rio Grande do Sul, Brazil.

External sources

  • No sources of support supplied

Declarations of interest

None known.

Notes

The CHBG Editorial team withdraws the protocol by Falavigna M, Kieling C, Wolff FH, Medeiros LRF, Cheinquer H. Antibiotics for hepatic encephalopathy [Protocol]. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD006314. DOI: 10.1002/14651858.CD006314 as of today, 25 July 2017 because the systematic review could not be developed on time, and a new team of authors overtook the review topic 28 June 2016. A completely new protocol was published in The Cochrane Library 24 July 2017 with the following citation: Jeyaraj R, Morgan MY, Gluud LL. Aminoglycosides and metronidazole for people with cirrhosis and hepatic encephalopathy (Protocol). Cochrane Database of Systematic Reviews 2017, Issue 7. Art. No.: CD012734. DOI: 10.1002/14651858.CD012734. We expect that the review will be developed and published within the following year and a half.

Withdrawn from publication for reasons stated in the review

References

Additional references

  1. Alexander T, Thomas K, Cherian AM, Kanakasabapathy A. Effect of three antibacterial drugs in lowering blood and stool ammonia production in hepatic encephalopathy. The Indian Journal of Medical Research 1992;96:292‐6. [PubMed] [Google Scholar]
  2. Als‐Nielsen B, Gluud LL, Gluud C. Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD003044. DOI: 10.1002/14651858.CD003044.pub2. [DOI] [PubMed]
  3. Als‐Nielsen B, Gluud LL, Gluud C. Dopaminergic agonists for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD003047. DOI: 10.1002/14651858.CD003047.pub2. [DOI] [PubMed]
  4. Als‐Nielsen B, Koretz RL, Kjaergard LL, Gluud C. Branched‐chain amino acids for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001939. DOI: 10.1002/14651858.CD001939. [DOI] [PubMed]
  5. Als‐Nielsen B, Gluud LL, Gluud C. Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD002798. DOI: 10.1002/14651858.CD002798.pub2. [DOI] [PubMed]
  6. Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ (Clinical Research Ed.) 2003;326:219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bosch J, Bruix J, Mas A, Navasa M, Rodes J. Rolling review: the treatment of major complications of cirrhosis. Alimentary Pharmacology & Therapeutics 1994;8:639‐57. [DOI] [PubMed] [Google Scholar]
  8. Bucci L, Palmieri GC. Double blind, double dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Current Medical Research and Opinion 1993;13:109‐18. [DOI] [PubMed] [Google Scholar]
  9. Butterworth RF. Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metabolic Brain Disease 2002;17:221‐7. [DOI] [PubMed] [Google Scholar]
  10. Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, et al. Comparison of lactulose and neomycin in the treatment of chronic portal‐systemic encephalopathy. Gastroenterology 1977;72:573‐83. [PubMed] [Google Scholar]
  11. Deeks JJ, Higgins JPT, Altman DG, editors. Analysing and presenting results. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]; Section 8. Chichester, UK: John Wiley & Sons, Ltd, 2005. [Google Scholar]
  12. Descombe JJ, Dubourg D, Picard M, Palazzini E. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. International Journal of Clinical Pharmacology Research 1994;14:51‐6. [PubMed] [Google Scholar]
  13. Piazza S, Gabriella Filippazzo M, Valenza LM, Morello S, Pastore L, Conti A, et al. Rifaximine versus neomycin in the treatment of portosystemic encephalopathy. The Italian Journal of Gastroenterology 1991;23:403‐7. [PubMed] [Google Scholar]
  14. Egger M, Davey‐Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ (Clinical Research Ed.) 1997;315:629‐34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fitz G. Hepatic encephalopathy, hepatopulmonary syndrome, coagulopathy and other complications of chronic liver disease. In: Feldman M, Friedman LS, Sleisenger MH editor(s). Sleisenger & Fordtran's Gastrointestinal and Liver Disease. 7th Edition. Philadelphia: Saunders, 2002. [Google Scholar]
  16. Gluud C, Als‐Nielsen B, D'Amico G, Fingerhut A, Gluud LL, Khan S, et al. Hepato‐Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)) 2006, Issue 3. Art. No.: LIVER.
  17. Higgins JP, Thompson SG, Deeks JJ, Altman D. Measuring inconsistency in meta‐analyses. BMJ (Clinical Research Ed.) 2003;327:557‐60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]. Chichester, UK: John Wiley & Sons, Ltd, 2005. [Google Scholar]
  19. Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ (Clinical Research Ed.) 1999;319:670‐4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. International Conference on Harmonisation of Technical Requiements for Registration of Pharmaceuticals for Human Use. Code of Federal Regulation & ICH Guidelines. Media: Parexel Barnett, 1997. [Google Scholar]
  21. James JH, Ziparo V, Jeppsson B, Fischer JE. Hyperammonaemia, plasma aminoacid imbalance, and blood‐brain aminoacid transport: a unified theory of portal‐systemic encephalopathy. Lancet 1979;2(8146):772‐5. [DOI] [PubMed] [Google Scholar]
  22. Kjaergard LL, Villumsen J, Gluud C. Reported methodological quality and discrepancies between large and small randomized trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9. [DOI] [PubMed] [Google Scholar]
  23. Mas A, Rodes J, Sunyer L, Rodrigo L, Planas R, Vargas V, et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double‐blind, double‐dummy, controlled clinical trial. Hepatology 2003;38:51‐8. [DOI] [PubMed] [Google Scholar]
  24. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. Lancet 1998;352:609‐13. [DOI] [PubMed] [Google Scholar]
  25. Mullen KD, Dasarathy S. Hepatic encephalopathy. In: Schiff ER, Sorrell MF, Maddrey WC editor(s). Schiff's diseases of the liver. 8th Edition. Lippincott‐Raven, 1999. [Google Scholar]
  26. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta‐analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17:2815‐34. [DOI] [PubMed] [Google Scholar]
  27. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 4.2 for Windows. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2003.
  28. Rodes J. Clinical manifestations and therapy of hepatic encephalopathy. Advances in Experimental Medicine and Biology 1993;341:39‐44. [DOI] [PubMed] [Google Scholar]
  29. Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches'. International Journal of Technology Assessment in Health Care 2003;19(4):591‐603. [DOI] [PubMed] [Google Scholar]
  30. Schiano TD, Bodenheimer HC. Complications of chronic liver disease. In: Friedman S, Grendell J, McQuaid K editor(s). Current Diagnosis & Treatment in Gastroenterology. 2nd Edition. Lange Current Series, 2002. [Google Scholar]
  31. Schulz KF, Chalmers I, Hayes R, Altman D. Empirical evidence of bias. JAMA 1995;273(5):408‐12. [DOI] [PubMed] [Google Scholar]
  32. Testa R, Eftimiadi C, Sukkar GS, Leo C, Rovida S, Schito GC, et al. A non‐absorbable rifamycin for the treatment of hepatic encephalopathy. Drugs Under Experimental and Clinical Research 1985;11:387‐92. [PubMed] [Google Scholar]
  33. Williams R, James OFW, Warnes TW, Morgan MY. Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double‐blind, randomized, dose‐finding multi‐centre study. European Journal of Gastroenterology & Hepatology 2000;12:203‐8. [DOI] [PubMed] [Google Scholar]
  34. Zeneroli ML, Avallone R, Corsi L, Venturini I, Baraldi C, Baraldi M. Management of hepatic encephalopathy: role of rifaximin. Chemotherapy 2005;51(Suppl 1):90‐5. [DOI] [PubMed] [Google Scholar]

Articles from The Cochrane Database of Systematic Reviews are provided here courtesy of Wiley

RESOURCES