Пробиотики для людей с печеночной энцефалопатией
Abstract
Background
Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient’s quality of life and daily functioning, and represent a significant burden on healthcare resources. Probiotics are live micro‐organisms, which when administered in adequate amounts, may confer a health benefit on the host.
Objectives
To determine the beneficial and harmful effects of probiotics in any dosage, compared with placebo or no intervention, or with any other treatment for people with any grade of acute or chronic hepatic encephalopathy. This review did not consider the primary prophylaxis of hepatic encephalopathy.
Search methods
We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, conference proceedings, reference lists of included trials, and the World Health Organization International Clinical Trials Registry Platform until June 2016.
Selection criteria
We included randomised clinical trials that compared probiotics in any dosage with placebo or no intervention, or with any other treatment in people with hepatic encephalopathy.
Data collection and analysis
We used standard methodological procedures expected by The Cochrane Collaboration. We conducted random‐effects model meta‐analysis due to obvious heterogeneity of participants and interventions. We defined a P value of 0.05 or less as significant. We expressed dichotomous outcomes as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI).
Main results
We included 21 trials with 1420 participants, of these, 14 were new trials. Fourteen trials compared a probiotic with placebo or no treatment, and seven trials compared a probiotic with lactulose. The trials used a variety of probiotics; the most commonly used group of probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration ranged from 10 days to 180 days. Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining 13 trials did not disclose their funding source. We classified 19 of the 21 trials at high risk of bias.
We found no effect on all‐cause mortality when probiotics were compared with placebo or no treatment (7 trials; 404 participants; RR 0.58, 95% CI 0.23 to 1.44; low‐quality evidence). No‐recovery (as measured by incomplete resolution of symptoms) was lower for participants treated with probiotic (10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate‐quality evidence). Adverse events were lower for participants treated with probiotic than with no intervention when considering the development of overt hepatic encephalopathy (10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low‐quality evidence), but effects on hospitalisation and change of/or withdrawal from treatment were uncertain (hospitalisation: 3 trials, 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very low‐quality evidence; change of/or withdrawal from treatment: 9 trials, 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low‐quality evidence). Probiotics may slightly improve quality of life compared with no intervention (3 trials; 115 participants; results not meta‐analysed; low‐quality evidence). Plasma ammonia concentration was lower for participants treated with probiotic (10 trials; 705 participants; MD ‐8.29 μmol/L, 95% CI ‐13.17 to ‐3.41; low‐quality evidence). There were no reports of septicaemia attributable to probiotic in any trial.
When probiotics were compared with lactulose, the effects on all‐cause mortality were uncertain (2 trials; 200 participants; RR 5.00, 95% CI 0.25 to 102.00; very low‐quality evidence); lack of recovery (7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very low‐quality evidence); adverse events considering the development of overt hepatic encephalopathy (6 trials; 420 participants; RR 1.17, 95% CI 0.63 to 2.17; very low‐quality evidence); hospitalisation (1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very low‐quality evidence); intolerance leading to discontinuation (3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low‐quality evidence); change of/or withdrawal from treatment (7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low‐quality evidence); quality of life (results not meta‐analysed; 1 trial; 69 participants); and plasma ammonia concentration overall (6 trials; 325 participants; MD ‐2.93 μmol/L, 95% CI ‐9.36 to 3.50; very low‐quality evidence). There were no reports of septicaemia attributable to probiotic in any trial.
Authors' conclusions
The majority of included trials suffered from a high risk of systematic error (‘bias’) and a high risk of random error (‘play of chance’). Accordingly, we consider the evidence to be of low quality. Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available evidence is very low. High‐quality randomised clinical trials with standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics.
PICO
Резюме на простом языке
Пробиотики для людей с печеночной энцефалопатией
Почему этот обзор важен
Печеночная энцефалопатия ‐ это нарушение функций головного мозга в результате печеночной недостаточности или портосистемного шунта или обоих. Как печеночная энцефалопатия (клинически выраженная), так и минимальная печеночная энцефалопатия (клинически не выраженная) существенно ухудшают качество жизни пациента и его ежедневного функционирования, и представляют собой значительное бремя для ресурсов здравоохранения. Пробиотики ‐ это живые микроорганизмы, которые при введении в адекватных количествах могут быть полезными для здоровья хозяина. Мы нашли и обобщили рандомизированные клинические испытания о пользе и вреде любого пробиотика в любой дозировке в сравнении с плацебо, или с отсутствием вмешательства, или с любым другим лечением у людей с любой степенью острой или хронической печеночной энцефалопатии.
Основные результаты
Доказательства актуальны на июнь 2016 года. Из 21 включенного исследования, с общим числом участников 1420, 14 исследований сравнивали пробиотик с плацебо или с отсутствием лечения, а в семи исследованиях сравнивали пробиотик с лактулозой. Длительность лечения в клинических испытаниях колебалась от 10 до 180 дней.
По сравнению с плацебо или отсутствием вмешательства, пробиотики, вероятно, улучшают восстановление и могут привести к улучшению в развитии выраженной печеночной энцефалопатии, качества жизни и плазменных концентраций аммиака, но могут и привести лишь к небольшой разнице в смертности или не привести в разнице в смертности. Пробиотики могут немного улучшить качество жизни, по сравнению с отсутствием вмешательства; однако, этот вывод базируется на трех испытаниях с низким качеством доказательств. Лучше ли пробиотики, чем лактулоза при печеночной энцефалопатии ‐ неизвестно, так как качество имеющихся доказательств было очень низким. Ни в одном испытании не было сообщений о сепсисе ввиду приема пробиотика. Нет доказательств увеличения числа неблагоприятных событий из‐за пробиотиков по сравнению с плацебо и лактулозой.
Финансирование
Восемь исследований объявили свой источник финансирования, шесть из которых были независимо финансируемыми и два финансировались промышленностью. Остальные 13 испытаний не раскрыли свой источник финансирования.
Недостатки обзора
Многие из включенных испытаний страдали высоким риском систематической ошибки ('смещения') и высоким риском случайной ошибки (‘случайности’). Соответственно, мы считаем, что эти доказательства низкого качества.
Выводы
По сравнению с плацебо или отсутствием вмешательства, пробиотики, вероятно, улучшают восстановление и могут привести к улучшению развития выраженной печеночной энцефалопатии, качества жизни и плазменных концентраций аммиака, но могут и привести лишь к небольшой разнице в смертности или ее отсутствию. Лучше ли пробиотики, чем лактулоза при печеночной энцефалопатии ‐ неизвестно, так как качество имеющихся доказательств было очень низким. Необходимы высококачественные рандомизированные клинические испытания со стандартизированным сбором и представлением данных, чтобы в дальнейшем прояснить истинную эффективность пробиотиков.
Authors' conclusions
Summary of findings
| Probiotic versus placebo or no intervention for people with hepatic encephalopathy | ||||||
| Patient or population: people with hepatic encephalopathy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo/no intervention | Risk with probiotic | |||||
| All‐cause mortality (follow‐up: 2 weeks to 3 months) | Study population | RR 0.58 | 404 | ⊕⊕⊝⊝ | ||
| 51 per 1000 | 30 per 1000 | |||||
| Moderate | ||||||
| 25 per 1000 | 14 per 1000 | |||||
| No‐recovery (incomplete resolution of clinical symptoms) (follow‐up: 1 month to 3 months) | Study population | RR 0.67 | 574 | ⊕⊕⊕⊝ | ||
| 790 per 1000 | 529 per 1000 | |||||
| Moderate | ||||||
| 877 per 1000 | 588 per 1000 | |||||
| Adverse events ‐ Overt hepatic encephalopathy (follow‐up: 2 weeks to 3 months) | Study population | RR 0.29 | 585 | ⊕⊕⊝⊝ | ||
| 168 per 1000 | 49 per 1000 | |||||
| Moderate | ||||||
| 169 per 1000 | 49 per 1000 | |||||
| Adverse events ‐ Change of/or withdrawal from treatment (follow‐up: 1 month to 3 months) | Study population | RR 0.70 | 551 | ⊕⊝⊝⊝ | ||
| 204 per 1000 | 143 per 1000 | |||||
| Moderate | ||||||
| 158 per 1000 | 111 per 1000 | |||||
| Quality of life (follow‐up: 1 month to 3 months) | — | — | — | 115 | ⊕⊕⊝⊝ | |
| Plasma ammonia concentration (final and change scores) (μmol/L) (follow‐up: 1 month to 6 months) | — | The mean plasma ammonia concentration (final and change scores) (μmol/L) in the intervention group was 8.29 fewer (13.17 fewer to 3.41 fewer). | — | 705 | ⊕⊕⊝⊝ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level for serious concerns or two levels for very serious concerns of imprecision (based on few events and wide confidence intervals). | ||||||
| Probiotic versus lactulose for people with hepatic encephalopathy | ||||||
| Patient or population: people with hepatic encephalopathy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with lactulose | Risk with probiotic | |||||
| All‐cause mortality (follow‐up: 1 month to 2 months) | Study population | RR 5.00 | 200 | ⊕⊝⊝⊝ | ||
| 0 per 1000 | 0 per 1000 | |||||
| No‐recovery (incomplete resolution of clinical symptoms) (follow‐up: 1 month to 3 months) | Study population | RR 1.01 | 430 | ⊕⊝⊝⊝ | ||
| 521 per 1000 | 526 per 1000 | |||||
| Moderate | ||||||
| 500 per 1000 | 505 per 1000 | |||||
| Adverse events ‐ Overt hepatic encephalopathy (follow‐up: 1 to 3 months) | Study population | RR 1.17 | 420 | ⊕⊝⊝⊝ | ||
| 81 per 1000 | 95 per 1000 | |||||
| Moderate | ||||||
| 60 per 1000 | 70 per 1000 | |||||
| Adverse events ‐ Change of/or withdrawal from treatment (follow‐up: 1 month to 3 months) | Study population | RR 1.27 | 490 | ⊕⊝⊝⊝ | ||
| 160 per 1000 | 203 per 1000 | |||||
| Moderate | ||||||
| 114 per 1000 | 145 per 1000 | |||||
| Quality of life (follow‐up: 1 month to 3 months) | It is uncertain whether probiotics improve quality of life because the available evidence is of very low quality. | — | 69 | ⊕⊝⊝⊝ | ||
| Plasma ammonia concentration (final and change scores) (μmol/L) (follow‐up: 1 month to 3 months) | — | The mean plasma ammonia concentration (final and change scores) (μmol/L) in the intervention group was 2.93 fewer (9.36 fewer to 3.5 more). | — | 325 | ⊕⊝⊝⊝ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one for serious concerns or two levels for very serious concerns of imprecision (small samples, very few events, and wide confidence intervals). | ||||||
Background
Description of the condition
Hepatic encephalopathy (also known as portosystemic encephalopathy) is a reversible neuropsychiatric disorder seen in the context of either acute or chronic liver failure or portosystemic shunting, or both (Ferenci 2002). Hepatic encephalopathy is characterised by complex cognitive dysfunction, which is independent of sleep dysfunction or problems with overall intelligence (Blei 2001). Minimal hepatic encephalopathy is a milder form of the same condition, which does not have obvious clinical signs (Stewart 2007; Bajaj 2011). The onset of hepatic encephalopathy indicates a poor prognostic outcome. It may also reduce quality of life and level of daily functioning (Groeneweg 1998; Arguedas 2003). 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 (Butterworth 1987; Blei 2001; Vaquero 2003). Current therapeutic options include intensive supportive care, identification and correction of the precipitating causes, tailored dietary restrictions, non‐absorbable disaccharides, L‐ornithine L‐aspartate, and/or oral antibiotics (Riordan 1997; Blei 2001; Als‐Nielsen 2003; Als‐Nielsen 2004a; Als‐Nielsen 2004b; Als‐Nielsen 2004c; Jiang 2009).
Description of the intervention
Probiotics are live micro‐organisms, which when administered in adequate amounts may confer a health benefit on the host (Schrezenmeir 2001). However, the dose needed to confer a health benefit is unknown for many conditions. Probiotics commonly come from two groups of bacteria, Lactobacillus or Bifidobacterium. Within each group, there are different species (e.g. Lactobacillus acidophilus and Bifidobacterium bifidus), and within each species, different strains (or varieties). A few common probiotics, such as Saccharomyces boulardii, are yeasts, which are different from bacteria. Therapeutic effects may be strain specific, and so caution must be exerted in generalising results from one species to another. While probiotics are generally considered safe, adverse events have been attributed to their use (Besselink 2008).
How the intervention might work
There is some evidence for an alteration in the composition of the gastrointestinal bacterial flora of people with liver disease (Rolfe 2000). Modulation of the gut microbiota is an important aspect of current therapy; the current conventional treatment option of the broad‐spectrum antibiotic rifaxamin is minimally absorbed and targets gram‐negative and gram‐positive enteric bacteria. Similarly, in addition to the osmotic effect of lactulose, which encourages removal of toxic metabolic products such as ammonia, it is also known to have a bifidogenic effect (De Preter 2006; Bass 2010). Amongst other potential reasons, one rationale behind the use of probiotics for hepatic encephalopathy is to reduce the prevalence of harmful ammonia‐producing bacteria in the gastrointestinal system. Probiotics are thought to reduce blood ammonia levels by several mechanisms including decreasing bacterial urease activity, decreasing ammonia absorption by decreasing pH, decreasing intestinal permeability, and improving nutritional status of gut epithelium (Poh 2012).
Why it is important to do this review
Hepatic encephalopathy significantly impairs patient’s quality of life and daily functioning, job performance, and overall mortality (Groeneweg 1998; Arguedas 2003; Stinton 2013). Caring for and treating patients with hepatic encephalopathy is a significant burden on the healthcare system. In 2005, hepatic encephalopathy cost the US healthcare system an estimated USD 4676.7 million, increasing to USD 7244.7 million in 2009 (Stepanova 2012). Previous Cochrane Hepato‐Biliary Group systematic reviews have only shown moderate, and in some cases no benefit for current or proposed therapies for hepatic encephalopathy, which include non‐absorbable disaccharides, oral antibiotics, branched‐chain amino acids, and dopamine (Als‐Nielsen 2003; Als‐Nielsen 2004a; Als‐Nielsen 2004b; Als‐Nielsen 2004c; Junker 2014; Gluud 2015). Based on a preliminary analysis, it is estimated that the literature on probiotics in hepatic encephalopathy has doubled since this systematic review was last published in 2011, hence this update will improve the evidence base on the use of probiotics in hepatic encephalopathy.
Objectives
To determine the beneficial and harmful effects of probiotics in any dosage, compared with placebo or no intervention or with any other treatment for people with any grade of acute or chronic hepatic encephalopathy. This review did not consider the primary prophylaxis of hepatic encephalopathy.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised trials that compared probiotics with placebo or no intervention, or with any other treatment for people with hepatic encephalopathy. We applied no restrictions on language of publication, publication date, or publication status. We excluded quasi‐randomised trials.
Types of participants
Inclusion criteria
We included all people with any grade of acute or chronic hepatic encephalopathy in connection with acute and chronic liver disease as well as acute hepatic failure, no matter the aetiology of liver disease or factors precipitating the hepatic encephalopathy.
Exclusion criteria
We excluded trials with participants in whom a diagnosis of hepatic encephalopathy was not confirmed, that is where altered mental status or cognitive function was not confirmed by a standardised neuropsychological assessment. Where co‐interventions such as medication were being administered, they had to be administered equally across the relevant intervention groups of the trial so that fair comparisons could be made.
Types of interventions
Any probiotic at any dose for any duration. Additional co‐interventions were allowed if received by all trial intervention groups and deemed sufficiently similar across trial groups. Where synbiotics were used (a combination of a prebiotic and a probiotic; a prebiotic is a substance that stimulates the growth of probiotics), the control group must have received a similar prebiotic to be included in the review, such that across trial groups the difference in intervention(s) was probiotic alone. For example, where probiotic and lactulose were compared to antibiotic plus lactulose, the comparison would have been probiotics versus antibiotic. If a trial compared probiotics and prebiotics versus prebiotics, the trial would have been considered a probiotic versus placebo trial, as the difference between the two groups would have been probiotic alone.
Types of outcome measures
We assessed all outcomes at time points reported by the authors, but, where possible, also summarised at one, two, three, six months, and one year.
Primary outcomes
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All‐cause mortality: number of participants dead.
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Number of participants who did not recover from hepatic encephalopathy (defined as incomplete resolution of clinical symptoms). We considered an individual to be 'completely resolved' if he or she was not in a state of hepatic encephalopathy based on the trial’s definition of hepatic encephalopathy used in the inclusion process.
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Adverse events: number and type of adverse events, defined as participants with any untoward medical occurrence. We summarised adverse events that led to treatment discontinuation and those that did not lead to treatment discontinuation separately. We defined serious adverse events according to the International Conference on Harmonisation (ICH) guidelines (ICH‐GCP 1997), as any event that led to death, was life‐threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability, and any important medical event that may have jeopardised the patient or required intervention to prevent it. We considered all other adverse events as non‐serious.
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Quality of life: as measured by the 36‐Item Short Form Health Survey (SF‐36) or other similar validated scales, such as the Sickness Impact Profile (SIP) (Brazier 1992; Ware 1994).
Secondary outcomes
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Change of or withdrawal from treatment: number of participants who changed/withdrew from their allocated treatment regimen.
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Sepsis: number of participants with one or more episodes of sepsis (confirmed by a positive blood culture).
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Change in plasma ammonia concentration.
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Duration of stay in hospital: measured in days.
Search methods for identification of studies
Electronic searches
For this update, we searched The Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2016), The Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE Ovid, Embase Ovid, and Science Citation Index Expanded (Web of Science) (Royle 2003) all on the 14th of June 2016. The search strategies with the time spans of the searches are given in Appendix 1. The search filter for randomised trials in MEDLINE (OvidSP) was created by Lefebvre 2011, and the search filter for randomised trials in Embase (OvidSP) was created by Sharon 2006.
We also searched the World Health Organization International Clinical Trial Registry Platform (WHO ICTRP) (www.who.int/ictrp) for ongoing and unpublished trials up to June 2016 using an advanced search for the condition 'hepatic encephalopathy' and intervention 'probiotic', and using an advanced search for the condition 'hepatic encephalopathy'. As a quality check, we searched the ClinicalTrials.gov database (clinicaltrials.gov/ct2/home) in September 2016, even though ClinicalTrials.gov is included as one of the registers within the WHO ICTRP portal.
Searching other resources
We handsearched the proceedings of three relevant conferences:
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American Association for the Study of Liver Disease (AASLD) from 2005 to 2014;
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European Association for the Study of the Liver (EASL) from 2005 to 2014;
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Digestive Diseases Week (DDW) from 2005 to 2014, using the keywords 'hepatic encephalopathy', 'probiotic', 'bifidobacterium', 'lactobacillus', and 'liver disease'.
We identified further trials through reference lists of relevant articles and by contacting content experts and authors of included trials. We applied no date or language restrictions. We translated non‐English language articles using Google Translate (translate.google.com.au/). Mandarin translations were provided by Sunny Wu.
Data collection and analysis
Selection of studies
Working independently, three review authors conducted trial selection and data extraction. None of the review authors was blinded to journal or author names. Disagreements were resolved by consensus.
Data extraction and management
We extracted the following information using a standardised data extraction form.
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General information: author(s), title, source, contact address, year of trial, country of trial, language of publication, year of publication.
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Trial characteristics: design (randomised clinical trial), randomisation method, manner of recruitment, sampling method, duration of intervention period, length of follow‐up, reason for and number of dropouts and withdrawals, adverse events.
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Participants: baseline characteristics of participants in treatment groups such as sex, age, prevalence of comorbidities (e.g. diabetes), inclusion and exclusion trial criteria.
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Trial setting: e.g. inpatient/outpatient department, emergency department.
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Detailed description of both the intervention and the comparison intervention, type, dose, and duration of probiotic(s).
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Outcomes: specific outcome reported, assessment instrument used, scoring range where appropriate.
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Any co‐interventions.
We entered data into Review Manager 5 software and checked the data for accuracy (RevMan 2011).
Assessment of risk of bias in included studies
We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2016). Methodological quality was defined as the confidence that the design and the report of the randomised clinical trial would restrict bias in the comparison of the treatment groups (Moher 1998). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012; Savović 2012a), we assessed the risk of bias of the trials using the following 'Risk of bias' domains.
Sequence generation
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Low risk of bias: the method used was either adequate (e.g. computer‐generated random numbers, table of random numbers) or unlikely to introduce bias.
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Unclear risk of bias: there was insufficient information to assess whether the method used was likely to introduce confounding.
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High risk of bias: the method used was not best practise for randomisation.
Allocation concealment
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Low risk of bias: the method used (e.g. central allocation) was unlikely to induce bias on the final observed effect.
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Unclear risk of bias: there was insufficient information to assess whether the method used was likely to induce bias on the estimate of effect.
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High risk of bias: the method used (e.g. open random allocation schedule) was likely to induce bias on the final observed effect.
Blinding of participants
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Low risk of bias: blinding was performed adequately, or the outcome was not likely to be influenced by lack of blinding.
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Unclear risk of bias: there was insufficient information to assess whether the type of blinding used was likely to induce bias on the effect.
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High risk of bias: no blinding or incomplete blinding, and the outcome was likely to be influenced by lack of blinding.
Blinding of personnel
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Low risk of bias: blinding was performed adequately, or the outcome was not likely to be influenced by lack of blinding.
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Unclear risk of bias: there was insufficient information to assess whether the type of blinding used was likely to induce bias on the effect.
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High risk of bias: no blinding or incomplete blinding, and the outcome was likely to be influenced by lack of blinding.
Blinding of outcome assessors
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Low risk of bias: blinding was performed adequately, or the outcome measurement was not likely to be influenced by lack of blinding.
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Unclear risk of bias: there was insufficient information to assess whether the type of blinding used was likely to induce bias on the estimate of effect.
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High risk of bias: no blinding or incomplete blinding, and the outcome measurement was likely to be influenced by lack of blinding.
Incomplete outcome data
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Low risk of bias: the underlying reasons for missing data were unlikely to cause treatment effects to depart from plausible values, or appropriate methods were employed to handle missing data.
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Unclear risk of bias: there was insufficient information to assess whether the missing‐data mechanism in combination with the method used to handle missing data was likely to induce bias on the estimate of effect.
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High risk of bias: the crude estimate of effects (e.g. complete‐case estimate) was clearly biased due to the underlying reasons for missing data, and the methods used to handle missing data were unsatisfactory.
Selective outcome reporting
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Low risk of bias: the trial protocol was available, or the study author provided further information about prespecified outcomes and all of the trial's prespecified outcomes that were of interest in the review were reported or similar.
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Unclear risk of bias: there was insufficient information to assess whether the magnitude and direction of the observed effect were related to selective outcome reporting.
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High risk of bias: not all of the trial's prespecified primary outcomes were reported or similar.
Other bias
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Low risk of bias: the trial was independently funded, e.g. by a government organisation or university.
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Unclear risk of bias: the trial did not declare its funding source.
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High risk of bias: the trial was industry funded, e.g. by a pharmaceutical company, or an author was an employee of a pharmaceutical company.
We considered trials judged as being at low risk of bias in all of the specified individual domains as trials at low risk of bias. We considered trials judged as being at unclear risk of bias or high risk of bias in one or more of the specified individual domains as trials at high risk of bias. We contacted authors of the original reports to provide further details when any of the above information was unclear.
Measures of treatment effect
We conducted data analysis according to the guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2016).
For dichotomous data, we presented results as summary risk ratio (RR) with 95% confidence intervals (CI). For continuous data, we presented results as mean difference (MD) if outcomes were measured in the same way amongst trials.
Unit of analysis issues
Trial participants as randomised per intervention group.
Dealing with missing data
Data for all participants were analysed in the group to which they are allocated, regardless of whether or not they received the allocated intervention. If in the original reports participants were not analysed in the group to which they were randomised and there was sufficient information in the trial report, we attempted to restore these participants to the correct group, that is we conducted intention‐to‐treat analysis where it was possible to do so. Where data were missing, we sought clarification from the authors of the trial. If intention‐to‐treat analysis was not possible, we conducted available‐case analysis or per‐protocol analysis.
Assessment of heterogeneity
We assessed heterogeneity amongst trials, when appropriate, using the I² and Cochran Q statistics. Where we detected substantial heterogeneity (I² more than 50% or P less than 0.10), we explored this heterogeneity by prespecified subgroup analysis and sensitivity analysis.
Assessment of reporting biases
Where we suspected reporting bias, we attempted to contact trial authors to provide the missing outcome data. When missing data were thought to potentially introduce serious bias, the impact of including such trials in the overall assessment of results was explored by a sensitivity analysis. Where there were at least 10 trials, we also used funnel plot asymmetry to assess the existence of bias.
Data synthesis
We conducted statistical analysis with random‐effects model meta‐analyses using Review Manager 5 software (RevMan 2011). We used random‐effects models for all analyses where trials examined the same intervention and the trials populations and methods were judged to be sufficiently similar. We originally planned to also conduct fixed‐effect model meta‐analysis, but abstained due to obvious heterogeneity of participants and intervention. We defined a P value of 0.05 or less as significant.
Subgroup analysis and investigation of heterogeneity
The following were priori subgroup analyses.
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Type of probiotic (by genus): Lactobacillus, Bifidobacteria, mixed, or unclear.
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Grade of hepatic encephalopathy: minimal compared to overt.
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Duration of therapy.
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MELD (Model for End‐Stage Liver Disease) score.
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Co‐interventions used.
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Trials with low risk of bias compared to trials with high risk of bias.
We assessed differences among subgroups by test of interaction (Altman 1996).
Sensitivity analysis
We carried out sensitivity analysis when we detected significant heterogeneity (I² more than 50% or P less than 0.10) to determine the source, that we sequentially removed trials from the analysis to determine which trial or trials were contributing to the heterogeneity.
'Summary of findings' tables
We used the GRADE system to evaluate the quality of the evidence for outcomes reported in the review, considering the within‐study risk of bias (methodological quality), inconsistency, imprecision, indirectness, and publication bias (GRADEpro).
We defined the levels of evidence as 'high', 'moderate', 'low', or 'very low':
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High certainty: this research provides a very good indication of the likely effect; the likelihood that the effect will be substantially different is low.
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Moderate certainty: this research provides a good indication of the likely effect; the likelihood that the effect will be substantially different is moderate.
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Low certainty: this research provides some indication of the likely effect; however, the likelihood that the effect will be substantially different is high.
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Very low certainty: this research does not provide a reliable indication of the likely effect; the likelihood that the effect will be substantially different is very high.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.
Results of the search
The process of identifying reports of randomised clinical trials for inclusion in the original review and in the review update is outlined in Figure 1.
Study flow diagram.
The original review published in 2011 included a total of seven trials reported in nine publications.
In this update, the electronic searches of the Cochrane Hepato‐Biliary Group Controlled Trials Register (n = 13), the Cochrane Central Register of Controlled Trials (CENTRAL) (n = 58), MEDLINE (n = 85), Embase (n = 272), and Science Citation Index Expanded (n = 291) identified a total of 719 publications. We identified six additional trials from reference list (n = 4) and trials registry (n = 3) searching.
After excluding 188 duplicates and 197 records overlapping with the original search, 341 unique records remained. Of these, we excluded 302 after reviewing titles and abstracts, and of the remaining 39 records, which we assessed after reviewing their full texts, we excluded a further 15 records. Three of the 39 records were identified as ongoing trials (ACTRN12610001021066; IRCT201211012417N9; NCT01798329); therefore, the results were not available for use in the review; information about these trials is provided in Characteristics of studies awaiting classification.
Consequently, the review update contributed an additional 14 new trials reported in 20 publications.
Seventeen reports were of 13 new trials (Loguercio 1995; Qiao 2010; Saji 2011; Dhiman 2013a; Zhao 2013; Zhitai 2013; Ziada 2013; Bajaj 2014a; Lunia 2014; Mouli 2014; Sharma 2014; Shavakhi 2014; Vlachogiannakos 2014). Three reports were of one previously excluded trial now included after we obtained the manuscript from the author (Nair 2008).
A total of 30 reports (publications and abstracts) of 21 trials qualified for inclusion in the review (Figure 1).
Four of these 21 trials were available as an abstract across four different reports (Dhiman 2013a; Zhitai 2013; Lunia 2014; Vlachogiannakos 2014), whilst 17 of these 21 trials were published in 26 different reports.
Included studies
Of the 21 included trials, 14 trials compared a probiotic with placebo or no treatment in 785 participants (Liu 2004; Bajaj 2008; Nair 2008; Malaguarnera 2010; Qiao 2010; Pereg 2011; Saji 2011; Dhiman 2013a; Zhitai 2013; Bajaj 2014a; Lunia 2014; Sharma 2014; Shavakhi 2014; Vlachogiannakos 2014). Three trials compared a probiotic with lactulose in 200 participants (Loguercio 1987; Loguercio 1995; Mouli 2014). Four trials compared a probiotic both with placebo and with lactulose in 435 participants (Sharma 2008; Mittal 2009; Zhao 2013; Ziada 2013).
The probiotics used in each trial are in Table 1.
| Study | Probiotics used |
|---|---|
| Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus, Lactobacillus casei, Bifidobacteria | |
| Lactobacillus GG AT strain 53103 | |
| VSL#3 (containing Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus, Streptococcus thermophilus) | |
| Pediacoccus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei, Lactobacillus plantarum | |
| Enterococcus lactic acid bacteria strain SF68 | |
| Enterococcus faecium strain SF68 | |
| VSL#3 (containing Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus) | |
| Bifidobacterium (subtype not available) | |
| VSL#3 (containing Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus) | |
| VSL#3 (4 strains of Lactobacillus (L acidophilus DSM 24735, L plantarum DSM 24730, L paracasei DSM 24733, L delbrueckii subsp. bulgaricus DSM 24734), 3 strains of Bifidobacterium (B longum DSM 24736, B breve DSM 24732, B infantis DSM 24737), and 1 strain of Streptococcus (S thermophilus DSM 24731)) | |
| Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, Saccharomyces boulardii | |
| Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium bifidum, Streptococcus thermophilus (Bio Plus, Supherb, Israel) | |
| Bifid triple viable (not further specified) | |
| Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, Saccharomyces boulardii | |
| Enterococcus faecalis, Clostridium butyricum, Bacillus mesentricus, lactic acid Bacillus | |
| Velgut ERIS Pharmaceuticals, Ahmadabad, India (Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus casei, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium breve, Saccharomyces boulardii, Streptococcus thermophilus) | |
| Balance (Protexin Co., Somerset, UK) Lactobacillus strains (L casei, L rhamnosus, L acidophilus, L bulgaricus), Bifidobacterium strains (B breve, B longum), and Streptococcus thermophilus | |
| Lactobacillus plantarum 299v | |
| Unclear | |
| Live Bacillus cereus capsules | |
| Lactobacillus acidophilus |
Seventeen trials enrolled participants with minimal hepatic encephalopathy (Liu 2004; Bajaj 2008; Nair 2008; Sharma 2008; Mittal 2009; Qiao 2010; Pereg 2011; Saji 2011; Dhiman 2013a; Zhao 2013; Ziada 2013; Bajaj 2014a; Lunia 2014; Mouli 2014; Sharma 2014; Shavakhi 2014; Vlachogiannakos 2014), and three trials enrolled participants with overt hepatic encephalopathy (grade I or II according to the West Haven criteria) (Loguercio 1987; Loguercio 1995; Malaguarnera 2010). The type of hepatic encephalopathy in one trial was unclear from the text (Zhitai 2013).
Excluded studies
We excluded a total of 320 newly identified and separate publications in the update. One previously excluded study was included after a manuscript containing further information was obtained from the author (Nair 2008).
Risk of bias in included studies
Reporting of trial methodology was incomplete for the majority of the domains, as summarised in Figure 2 and Figure 3. We classified most trials at a high risk of bias (with the exception of Bajaj 2014a and Nair 2008).
Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.
Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
Allocation
Sequence generation was adequately performed in 12 trials (Loguercio 1995; Bajaj 2008; Nair 2008; Sharma 2008; Mittal 2009; Malaguarnera 2010; Saji 2011; Zhao 2013; Bajaj 2014a; Mouli 2014; Sharma 2014; Shavakhi 2014), inadequately performed in one trial (Liu 2004), and unclear in eight trials (Loguercio 1987; Qiao 2010; Pereg 2011; Dhiman 2013a; Zhitai 2013; Ziada 2013; Lunia 2014; Vlachogiannakos 2014).
Seven trials reported adequate allocation concealment (Loguercio 1995; Liu 2004; Nair 2008; Mittal 2009; Bajaj 2014a; Mouli 2014; Sharma 2014), two trials reported inadequate allocation concealment (Bajaj 2008; Sharma 2008), and 12 trials were unclear about their method of allocation concealment (Loguercio 1987; Malaguarnera 2010; Qiao 2010; Pereg 2011; Saji 2011; Dhiman 2013a; Zhao 2013; Zhitai 2013; Ziada 2013; Lunia 2014; Shavakhi 2014; Vlachogiannakos 2014).
Blinding
Three trials reported adequate blinding of participants, outcome assessors, and personnel (Loguercio 1987; Nair 2008; Bajaj 2014a). One trial reported adequate blinding of outcome assessors and participants, but was unclear regarding blinding of personnel (Saji 2011). Three trials reported adequate blinding of outcome assessors, but reported no blinding of participants and personnel (Bajaj 2008; Ziada 2013; Mouli 2014). One trial was unclear regarding blinding of outcome assessors, but reported no blinding of participants and personnel (Shavakhi 2014). One trial reported blinding of participants, but was unclear regarding blinding of personnel and outcome assessors (Vlachogiannakos 2014). Three trials did not blind participants, personnel, or outcome assessors (Sharma 2008; Mittal 2009; Sharma 2014). The remaining nine trials were unclear regarding the conduct of blinding (Loguercio 1995; Liu 2004; Malaguarnera 2010; Qiao 2010; Pereg 2011; Dhiman 2013a; Zhao 2013; Zhitai 2013; Lunia 2014).
Incomplete outcome data
Incomplete outcome data were adequately addressed in six trials (Bajaj 2008; Nair 2008; Saji 2011; Ziada 2013; Bajaj 2014a; Shavakhi 2014), inadequately addressed in four trials (Loguercio 1987; Loguercio 1995; Sharma 2008; Pereg 2011), and unclear in the remaining trials (Liu 2004; Mittal 2009; Malaguarnera 2010; Qiao 2010; Dhiman 2013a; Zhao 2013; Zhitai 2013; Lunia 2014; Mouli 2014; Sharma 2014; Vlachogiannakos 2014).
Selective reporting
Four trials were free of selective outcome reporting (Bajaj 2008; Sharma 2008; Saji 2011; Mouli 2014), while the remaining 17 trials were unclear (Loguercio 1987; Loguercio 1995; Liu 2004; Nair 2008; Mittal 2009; Malaguarnera 2010; Qiao 2010; Pereg 2011; Dhiman 2013a; Zhao 2013; Zhitai 2013; Ziada 2013; Bajaj 2014a; Lunia 2014; Sharma 2014; Shavakhi 2014; Vlachogiannakos 2014).
Other potential sources of bias
Eight trials declared their funding source (Loguercio 1987; Bajaj 2008; Nair 2008; Pereg 2011; Bajaj 2014a; Mouli 2014; Sharma 2014; Shavakhi 2014), of which six were independently funded (Bajaj 2008; Nair 2008; Bajaj 2014a; Mouli 2014; Sharma 2014; Shavakhi 2014), and two were industry funded (Loguercio 1987; Pereg 2011). The remaining trials did not disclose their funding source (Loguercio 1995; Liu 2004; Sharma 2008; Mittal 2009; Malaguarnera 2010; Qiao 2010; Saji 2011; Dhiman 2013a; Zhao 2013; Zhitai 2013; Ziada 2013; Lunia 2014; Vlachogiannakos 2014).
Effects of interventions
See: Summary of findings 1 Probiotic for people with hepatic encephalopathy; Summary of findings 2 Probiotics for people with hepatic encephalopathy
Probiotic versus placebo or no treatment
Primary outcomes
All‐cause mortality
There were no significant differences in all‐cause mortality (Analysis 1.1; 7 trials; 404 participants; RR 0.58, 95% CI 0.23 to 1.44; low quality of evidence).
Number of participants who did not recover from hepatic encephalopathy
No‐recovery (as measured by incomplete resolution of symptoms) was significantly lower for participants treated with probiotic than with placebo or no intervention overall (Analysis 1.2; 10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate quality of evidence), at one month (Analysis 1.2 (Analysis 1.2.1); 4 trials; 228 participants; RR 0.75, 95% CI 0.58 to 0.96), and at three months (Analysis 1.2 (Analysis 1.2.3); 3 trials; 229 participants; RR 0.58, 95% CI 0.43 to 0.78), but not at two months (Analysis 1.2 (Analysis 1.2.2); 3 trials; 117 participants; RR 0.65, 95% CI 0.38 to 1.10).
Adverse events
Adverse events were lower for participants treated with probiotic than with placebo or no intervention when considering the development of overt hepatic encephalopathy (Analysis 1.3 (Analysis 1.3.1); 10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low quality of evidence), but there were no significant differences for hospitalisation (Analysis 1.3 (Analysis 1.3.3); 3 trials; 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very low quality of evidence) or change of/or withdrawal from treatment (Analysis 1.3 (Analysis 1.3.5); 9 trials; 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low quality of evidence).
Quality of life
There were no significant differences in quality of life scores for participants treated with probiotic than with no intervention in the SF‐36 Physical Functioning Scale (Analysis 1.4 (Analysis 1.4.1); 1 trial; 20 participants; MD 0.00, 95% CI ‐5.47 to 5.47; low quality of evidence) and the SF‐36 Mental Health Scale (Analysis 1.4 (Analysis 1.4.2); 1 trial; 20 participants; MD ‐4.00, 95% CI ‐9.82 to 1.82; low quality of evidence). There was no significant difference in quality of life score for participants treated with probiotic than with no intervention in the Total Sickness Impact Profile (SIP) Score (Analysis 1.4 (Analysis 1.4.3); 2 trials; 95 participants; MD ‐3.66, 95% CI ‐7.75 to 0.44; low quality of evidence), but there were significant differences for change in SIP Psychological Score (Analysis 1.4 (Analysis 1.4.4); 2 trials; 95 participants; MD ‐3.54, 95% CI ‐4.95 to ‐2.12; low quality of evidence) and change in SIP Physical Score (Analysis 1.4 (Analysis 1.4.5); 2 trials; 95 participants; MD ‐2.94, 95% CI ‐4.44 to ‐1.44; low quality of evidence). A reduced SIP score indicates improved quality of life.
Secondary outcomes
Sepsis
There were no reports of septicaemia attributable to probiotic in any trial.
Change in plasma ammonia concentration
Plasma ammonia concentration was significantly lower for participants treated with probiotic than with no intervention overall (Analysis 1.5; 10 trials; 705 participants; MD ‐8.29 μmol/L, 95% CI ‐13.17 to ‐3.41; low quality of evidence), at one month (Analysis 1.5 (Analysis 1.5.1); 5 trials; 357 participants; MD ‐5.55 μmol/L, 95% CI ‐10.67 to ‐0.42), at three months (Analysis 1.5 (Analysis 1.5.3); 1 trial; 73 participants; MD ‐6.79 μmol/L, 95% CI ‐10.39 to ‐3.19), and at six months (Analysis 1.5 (Analysis 1.5.3); 1 trial; 64 participants; MD ‐31.08 μmol/L, 95% CI ‐40.50 to ‐21.66), but not at two months (Analysis 1.5 (Analysis 1.5.2); 4 trials; 211 participants; MD ‐5.11 μmol/L, 95% CI ‐14.56 to 4.34).
Duration of hospital stay: measured in days
No trials reported duration of hospital stay.
Subgroup analysis
We performed subgroup analyses for the outcomes no‐recovery (Analysis 1.2) and plasma ammonia concentration (Analysis 1.5) using the prespecified subgroups (Subgroup analysis and investigation of heterogeneity). We could not perform subgroup analyses by MELD score, as most trials did not report this, or by risk of bias, as we judged most trials at high risk of bias.
No‐recovery
We detected no significant differences for the following subgroup analyses: type of probiotic used, test for subgroup differences: Chi² = 0.74, df = 2 (P = 0.69); grade of hepatic encephalopathy, test for subgroup differences: Chi² = 3.56, df = 1 (P = 0.06); duration of therapy, test for subgroup differences: Chi² = 1.68, df = 2 (P = 0.43); co‐interventions used, test for subgroup differences: Chi² = 3.57, df = 2 (P = 0.17) (Table 2).
| Probiotic versus placebo or no intervention | ||||
|---|---|---|---|---|
| No‐recovery | Studies | Participants | Effect estimate Risk ratio [95% CI] | Difference P |
| Type of probiotic | 10 | 574 | — | 0.69 |
| Lactobacillus | 4 | 195 | 0.67 [0.45, 1.00] | — |
| Mixed | 5 | 309 | 0.65 [0.50, 0.83] | — |
| Unclear | 1 | 70 | 0.76 [0.58, 0.98] | — |
| Grade of hepatic encephalopathy | 10 | 574 | — | 0.06 |
| Minimal | 8 | 473 | 0.63 [0.52, 0.76] | — |
| Overt | 2 | 101 | 0.98 [0.64, 1.48] | — |
| Duration of therapy | 10 | 574 | — | 0.43 |
| <= 1 month | 4 | 228 | 0.75 [0.58, 0.96] | — |
| 1 > 2 months | 3 | 117 | 0.65 [0.38, 1.10] | — |
| 2 + months | 3 | 229 | 0.58 [0.43, 0.78] | — |
| Co‐interventions | 10 | 574 | — | 0.17 |
| No treatment | 8 | 473 | 0.63 [0.52, 0.76] | — |
| Bioactive fermentable fibre | 1 | 40 | 1.00 [0.54, 1.86] | — |
| Lactulose | 1 | 61 | 0.96 [0.55, 1.69] | — |
| Plasma ammonia concentration | Studies | Participants | Effect estimate Mean difference [95% CI] | Difference P |
| Type of probiotic | 10 | 580 | — | 0.35 |
| Bifidobacterium | 1 | 125 | ‐9.35 [‐16.09, ‐2.61] | — |
| Lactobacillus | 3 | 121 | ‐11.90 [‐24.41, 0.60] | — |
| Mixed | 4 | 190 | ‐1.80 [‐9.65, 6.06] | — |
| Unclear | 2 | 144 | ‐17.02 [‐44.07, 10.02] | — |
| Grade of hepatic encephalopathy | 10 | 580 | — | 0.85 |
| Minimal | 9 | 455 | ‐8.50 [‐14.38, ‐2.62] | — |
| Overt | 1 | 125 | ‐9.35 [‐16.09, ‐2.61] | — |
| Duration of therapy | 10 | 580 | — | 0.58 |
| <=1 month | 4 | 232 | ‐5.93 [‐12.25, 0.39] | — |
| 1 > 2 months | 4 | 211 | ‐5.11 [‐14.56, 4.34] | — |
| 2 + months | 2 | 137 | ‐18.53 [‐42.32, 5.26] | — |
| Co‐interventions used | 10 | 580 | — | 0.11 |
| No treatment | 7 | 354 | ‐10.42 [‐18.68, ‐2.17] | — |
| Bioactive fermentable fibre | 1 | 40 | ‐2.90 [‐5.51, ‐0.29] | — |
| Lactulose | 2 | 186 | ‐7.88 [‐14.29, ‐1.47] | — |
| Probiotic versus lactulose | ||||
| Plasma ammonia concentration | Studies | Participants | Effect estimate Mean difference [95% CI] | Difference P |
| Type of probiotic | 6 | 325 | — | 0.13 |
| Enterococcus SF68 | 2 | 56 | ‐12.83 [‐24.51, ‐1.15] | — |
| Mixed | 2 | 139 | 1.34 [‐1.72, 4.40] | — |
| Lactobacillus | 1 | 50 | ‐3.17 [‐17.17, 10.83] | — |
| Unclear | 1 | 80 | 1.31 [‐5.70, 8.32] | — |
| Grade of hepatic encephalopathy | 6 | 325 | — | 0.02 |
| Minimal | 4 | 269 | 1.16 [‐1.59, 3.91] | — |
| Overt | 2 | 56 | ‐12.83 [‐24.51, ‐1.15] | — |
CI: confidence interval
Plasma ammonia
We detected no significant differences for the following subgroup analyses: type of probiotic used, test for subgroup differences: Chi² = 3.26, df = 3 (P = 0.35); grade of hepatic encephalopathy, test for subgroup differences: Chi² = 0.03, df = 1 (P = 0.85); duration of therapy, test for subgroup differences: Chi² = 1.09, df = 2 (P = 0.58); co‐interventions used, test for subgroup differences: Chi² = 4.40, df = 2 (P = 0.11) (Table 2).
Quality of the evidence
In the analyses comparing probiotic versus placebo or no intervention (summary of findings Table 1), we downgraded the quality of the evidence to 'moderate' for the outcome no‐recovery because the included trials were at high risk of bias. Likewise, we downgraded the quality of the evidence for the outcomes adverse events ‐‐ overt hepatic encephalopathy and plasma ammonia concentration to low because the included trials were at high risk of bias and the results were inconsistent. We downgraded the quality of the evidence for the outcomes all‐cause mortality and adverse events ‐‐ change of or withdrawal from treatment or both ‐‐ to very low because the included trials were at high risk of bias and the results were inconsistent or imprecise, or both.
Heterogeneity
Heterogeneity was demonstrated for the outcome no‐recovery (Analysis 1.2) (Chi² = 17.48, df = 9 (P = 0.04); I² = 48%) and did not seem attributable to type of probiotic used, grade of hepatic encephalopathy, duration of therapy, or co‐interventions used. Heterogeneity was demonstrated for the outcome plasma ammonia concentration (Analysis 1.5) (Chi² = 47.32, df = 9 (P < 0.00001); I² = 81%) and did not seem attributable to type of probiotic used, grade of hepatic encephalopathy, duration of therapy, or co‐interventions used (Table 2).
Probiotic versus lactulose
Primary outcomes
All‐cause mortality
There were no significant differences in all‐cause mortality (Analysis 2.1; 2 trials; 200 participants; RR 5.00, 95% CI 0.25 to 102.00; very low quality of evidence).
Number of participants who did not recover from hepatic encephalopathy
There was no significant difference in lack of recovery (Analysis 2.2; 7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very low quality of evidence).
Adverse events
There was no significant difference between participants treated with probiotic and those treated with lactulose for adverse events when considering the development of overt hepatic encephalopathy (Analysis 2.3 (Analysis 2.3.1); 6 trials; 420 participants; RR 1.17, 95% CI 0.63 to 2.17; very low quality of evidence), hospitalisation (Analysis 2.3 (Analysis 2.3.3); 1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very low quality of evidence), intolerance leading to discontinuation (Analysis 2.3 (Analysis 2.3.4); 3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low quality of evidence), or change of/or withdrawal from treatment (Analysis 2.3 (Analysis 2.3.5); 7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low quality of evidence).
Quality of life
There were no significant differences in quality of life scores between participants treated with probiotic and those treated with lactulose in change in Total SIP Score (Analysis 2.4 (Analysis 2.4.1); 1 trial; 69 participants; MD 0.65, 95% CI ‐1.13 to 2.43; very low quality of evidence); change in SIP Psychological Score (Analysis 2.4 (Analysis 2.4.2); 1 trial; 69 participants; MD 0.48, 95% CI ‐1.04 to 2.00; very low quality of evidence), or change in SIP Physical Score (Analysis 2.4 (Analysis 2.4.3); 1 trial; 69 participants; MD 0.38, 95% CI ‐0.61 to 1.37; very low quality of evidence).
Secondary outcomes
Sepsis
There were no reports of septicaemia attributable to probiotic in any trial.
Change in plasma ammonia concentration
There was no significant difference in plasma ammonia concentration overall (Analysis 2.5; 6 trials; 325 participants; MD ‐2.93 μmol/L, 95% CI ‐9.36 to 3.50; very low quality of evidence), at one month or less (Analysis 2.5 (Analysis 2.5.1); 5 trials; 248 participants; MD ‐4.30 μmol/L, 95% CI ‐13.17 to 4.56), or at three months (Analysis 2.5 (Analysis 2.5.2); 1 trial; 77 participants; MD 1.16 μmol/L, 95% CI ‐1.96 to 4.28).
Duration of hospital stay: measured in days
No trial reported duration of hospital stay.
Subgroup analysis
We performed subgroup analyses for the outcome plasma ammonia concentration (Analysis 2.5) using the prespecified subgroups (Subgroup analysis and investigation of heterogeneity).
We did not perform subgroup analyses by MELD score as this was not reported in most trials, nor by risk of bias as the majority of the trials were at high risk of bias.
Plasma ammonia
We detected a significant difference for the subgroup analyses on grade of hepatic encephalopathy, test for subgroup differences: Chi² = 5.22, df = 1 (P = 0.02); I² = 80.9%. We detected no significant difference for the subgroup analyses on type of probiotic used, test for subgroup differences: Chi² = 5.60, df = 3 (P = 0.13) (Table 2).
Quality of the evidence
In the analyses comparing probiotic versus lactulose (summary of findings Table 2), we downgraded the quality of the evidence to very low for all outcomes due to concerns that the included trials were at high risk of bias, the results were inconsistent or imprecise or both, and because a surrogate marker was used for clinically important outcomes.
Heterogeneity
Heterogeneity was demonstrated for the outcome plasma ammonia concentration (Analysis 2.5) (Chi² = 11.87, df = 4 (P = 0.02); I² = 66%). Heterogeneity seemed largely attributable to the grade of hepatic encephalopathy, and it did not seem attributable to the type of probiotic used (Table 2).
Discussion
Summary of main results
We included 21 trials with a total of 1420 randomised participants. The trials used a variety of probiotics, although the most commonly used probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration of the experimental intervention varied from 10 days to 180 days. We classified 19 of 21 trials as having a high risk of bias.
Probiotics may lead to little or no difference in mortality from any cause compared with no treatment. Probiotics probably improve recovery from hepatic encephalopathy (as measured by resolution of symptoms) compared with no treatment. Probiotics may prevent the development of overt hepatic encephalopathy compared with no treatment. The effects of probiotics on change of/or withdrawal from treatment is uncertain because the quality of the evidence was very low. Quality of life may slightly improve for patients treated with probiotic than with no intervention. Plasma ammonia concentration may decrease for patients treated with probiotic than with no intervention. No trial reported duration of hospital stay.
It is uncertain whether probiotics are better than lactulose for the management of hepatic encephalopathy, because the available evidence was of very low quality across all outcomes. There were no reports of septicaemia attributable to probiotic in any trial.
Overall completeness and applicability of evidence
The number of trials and randomised participants included in this review has substantially increased with this update. However, data from some trials were only available in abstract form; outcomes were often inconsistently reported; and most trials were at high risk of bias and included few participants. There is thus limited evidence for the use of probiotics as a treatment for people with hepatic encephalopathy. Overall, there is a large number of trials on probiotic use in cirrhosis (without confirmed diagnosis of hepatic encephalopathy). We have not considered trials of primary or secondary prevention using probiotics as prophylaxis against hepatic encephalopathy in the present review, which ought to be the subject of another systematic review. Also, trials on synbiotics should be considered for inclusion in the future alongside probiotics as a separate subgroup to illustrate comparative efficacy.
Quality of the evidence
Although compared to the original 2011 review the quantity of evidence has increased, the quality of evidence has lagged behind and is far from optimal. Although there may be emerging evidence for probiotic use, the quality of evidence for their use is low. Further randomised clinical trials with improved methodological quality and outcome data collection and data reporting are required to fully establish the role of probiotics in hepatic encephalopathy. The use of tools that quantify the statistical reliability of data across cumulative meta‐analysis such as Trial Sequential Analysis, TSA 2011, ought to be included in future updates (Wetterslev 2008; Thorlund 2011). We also need to search data‐bases of regulatory authorities for additional trials.
Potential biases in the review process
This systematic review with meta‐analysis was undertaken with broad inclusion criteria to assess the totality of available evidence. Our literature search was comprehensive and did not exclude trials based on language of publication or publication status. We attempted to contact authors wherever trial data and methodology were unclear. All data extraction and analysis was undertaken by several authors working independently to minimise bias. Despite these strengths, there were some limitations: for example, we were not blinded to authorship during data extraction and 'Risk of bias' assessment. While we did attempt to contact study authors, we were not always certain that our messages were received, and we did not attempt to make any further contact if we received no response to our initial emails. As stated above, we might have missed trials by not searching databases of regulatory authorities, and we did not control risks of random errors.
Agreements and disagreements with other studies or reviews
A review published in 2011 discusses the effects of prebiotics, probiotics, and synbiotics in minimal hepatic encephalopathy (Shukla 2011a). As our review did not evaluate the combination of probiotics, prebiotics, and synbiotics, it is not possible to make direct comparisons between the reviews. Of note, the Shukla 2011a review was only able to locate two trials of probiotics including participants with minimal hepatic encephalopathy, compared to the five trials in the previous version of our review (McGee 2011), suggesting that we utilised a more sensitive search strategy.
A 2011 meta‐analysis found improvement in “clinical and biochemical parameters in patients with minimal hepatic encephalopathy” and a “decrease the morbidity of clinical hepatic encephalopathy” (Tang 2011). However, that study used the time of Number Connection Test as a surrogate for clinical resolution of symptoms. In addition, they used a fixed‐effect model, while we used the random‐effects model in our review.
A 2012 review published a study, Holte 2012, with results largely similar to the initial 2011 publication of our systematic review and meta‐analysis (McGee 2011).
A meta‐analysis published in 2015 included nine randomised clinical trials comparing probiotic against placebo or no treatment (Zhao 2015). The authors concluded that probiotics were “associated with improvement of minimal hepatic encephalopathy, prophylaxis of overt hepatic encephalopathy, and reduction of SIP score and severe adverse events”, and our findings mirror these findings to some extent. They grouped serious adverse events as any of “minimal hepatic encephalopathy developing into overt hepatic encephalopathy, hospitalisations, infections, or unrelated emergency room (ER) visits”. However, we have separated these adverse events into subgroups, and found a significant difference favouring probiotics only for reducing the progression to overt hepatic encephalopathy, and not for the other serious adverse events. Furthermore, we have graded our findings to reflect the quality of the available evidence and the subsequent uncertainty around the results. In addition, due to the small sample sizes involved, random error or chance findings may partly explain the observed differences. Our review did not address the issue of prophylaxis of hepatic encephalopathy.
Another 2015 meta‐analysis of probiotic use in hepatic encephalopathy included observational data as well as randomised clinical trials, but found only 14 studies, where we have included 21 randomised clinical trials (Saab 2015). Saab and colleagues found that when probiotics were compared with placebo, there was a significant improvement in minimal hepatic encephalopathy and decreased progression to overt hepatic encephalopathy, which is consistent with our findings. This study also reported no significant difference in improvement of minimal hepatic encephalopathy, hospitalisation rates, or progression to overt hepatic encephalopathy when probiotics were compared with lactulose, which is again consistent with our findings. However, the Saab study noted significantly decreased hospitalisation rates when probiotics were compared with placebo, which we did not. This is likely due to bias from their observational data and incomplete evidence synthesis.
Study flow diagram.
Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.
Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
Comparison 1: Probiotic versus placebo or no intervention, Outcome 1: All‐cause mortality
Comparison 1: Probiotic versus placebo or no intervention, Outcome 2: No recovery (incomplete resolution of clinical symptoms)
Comparison 1: Probiotic versus placebo or no intervention, Outcome 3: Adverse events
Comparison 1: Probiotic versus placebo or no intervention, Outcome 4: Quality of life
Comparison 1: Probiotic versus placebo or no intervention, Outcome 5: Plasma ammonia concentration (final and change scores) (μmol/L)
Comparison 2: Probiotic versus lactulose, Outcome 1: All‐cause mortality
Comparison 2: Probiotic versus lactulose, Outcome 2: No recovery (incomplete resolution of clinical symptoms)
Comparison 2: Probiotic versus lactulose, Outcome 3: Adverse events
Comparison 2: Probiotic versus lactulose, Outcome 4: Health‐related quality of life
Comparison 2: Probiotic versus lactulose, Outcome 5: Plasma ammonia concentration (final and change scores) (μmol/L)
| Probiotic versus placebo or no intervention for people with hepatic encephalopathy | ||||||
| Patient or population: people with hepatic encephalopathy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo/no intervention | Risk with probiotic | |||||
| All‐cause mortality (follow‐up: 2 weeks to 3 months) | Study population | RR 0.58 | 404 | ⊕⊕⊝⊝ | ||
| 51 per 1000 | 30 per 1000 | |||||
| Moderate | ||||||
| 25 per 1000 | 14 per 1000 | |||||
| No‐recovery (incomplete resolution of clinical symptoms) (follow‐up: 1 month to 3 months) | Study population | RR 0.67 | 574 | ⊕⊕⊕⊝ | ||
| 790 per 1000 | 529 per 1000 | |||||
| Moderate | ||||||
| 877 per 1000 | 588 per 1000 | |||||
| Adverse events ‐ Overt hepatic encephalopathy (follow‐up: 2 weeks to 3 months) | Study population | RR 0.29 | 585 | ⊕⊕⊝⊝ | ||
| 168 per 1000 | 49 per 1000 | |||||
| Moderate | ||||||
| 169 per 1000 | 49 per 1000 | |||||
| Adverse events ‐ Change of/or withdrawal from treatment (follow‐up: 1 month to 3 months) | Study population | RR 0.70 | 551 | ⊕⊝⊝⊝ | ||
| 204 per 1000 | 143 per 1000 | |||||
| Moderate | ||||||
| 158 per 1000 | 111 per 1000 | |||||
| Quality of life (follow‐up: 1 month to 3 months) | — | — | — | 115 | ⊕⊕⊝⊝ | |
| Plasma ammonia concentration (final and change scores) (μmol/L) (follow‐up: 1 month to 6 months) | — | The mean plasma ammonia concentration (final and change scores) (μmol/L) in the intervention group was 8.29 fewer (13.17 fewer to 3.41 fewer). | — | 705 | ⊕⊕⊝⊝ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level for serious concerns or two levels for very serious concerns of imprecision (based on few events and wide confidence intervals). | ||||||
| Probiotic versus lactulose for people with hepatic encephalopathy | ||||||
| Patient or population: people with hepatic encephalopathy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with lactulose | Risk with probiotic | |||||
| All‐cause mortality (follow‐up: 1 month to 2 months) | Study population | RR 5.00 | 200 | ⊕⊝⊝⊝ | ||
| 0 per 1000 | 0 per 1000 | |||||
| No‐recovery (incomplete resolution of clinical symptoms) (follow‐up: 1 month to 3 months) | Study population | RR 1.01 | 430 | ⊕⊝⊝⊝ | ||
| 521 per 1000 | 526 per 1000 | |||||
| Moderate | ||||||
| 500 per 1000 | 505 per 1000 | |||||
| Adverse events ‐ Overt hepatic encephalopathy (follow‐up: 1 to 3 months) | Study population | RR 1.17 | 420 | ⊕⊝⊝⊝ | ||
| 81 per 1000 | 95 per 1000 | |||||
| Moderate | ||||||
| 60 per 1000 | 70 per 1000 | |||||
| Adverse events ‐ Change of/or withdrawal from treatment (follow‐up: 1 month to 3 months) | Study population | RR 1.27 | 490 | ⊕⊝⊝⊝ | ||
| 160 per 1000 | 203 per 1000 | |||||
| Moderate | ||||||
| 114 per 1000 | 145 per 1000 | |||||
| Quality of life (follow‐up: 1 month to 3 months) | It is uncertain whether probiotics improve quality of life because the available evidence is of very low quality. | — | 69 | ⊕⊝⊝⊝ | ||
| Plasma ammonia concentration (final and change scores) (μmol/L) (follow‐up: 1 month to 3 months) | — | The mean plasma ammonia concentration (final and change scores) (μmol/L) in the intervention group was 2.93 fewer (9.36 fewer to 3.5 more). | — | 325 | ⊕⊝⊝⊝ | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one for serious concerns or two levels for very serious concerns of imprecision (small samples, very few events, and wide confidence intervals). | ||||||
| Study | Probiotics used |
|---|---|
| Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus, Lactobacillus casei, Bifidobacteria | |
| Lactobacillus GG AT strain 53103 | |
| VSL#3 (containing Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus, Streptococcus thermophilus) | |
| Pediacoccus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei, Lactobacillus plantarum | |
| Enterococcus lactic acid bacteria strain SF68 | |
| Enterococcus faecium strain SF68 | |
| VSL#3 (containing Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus) | |
| Bifidobacterium (subtype not available) | |
| VSL#3 (containing Streptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus) | |
| VSL#3 (4 strains of Lactobacillus (L acidophilus DSM 24735, L plantarum DSM 24730, L paracasei DSM 24733, L delbrueckii subsp. bulgaricus DSM 24734), 3 strains of Bifidobacterium (B longum DSM 24736, B breve DSM 24732, B infantis DSM 24737), and 1 strain of Streptococcus (S thermophilus DSM 24731)) | |
| Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, Saccharomyces boulardii | |
| Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium bifidum, Streptococcus thermophilus (Bio Plus, Supherb, Israel) | |
| Bifid triple viable (not further specified) | |
| Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, Saccharomyces boulardii | |
| Enterococcus faecalis, Clostridium butyricum, Bacillus mesentricus, lactic acid Bacillus | |
| Velgut ERIS Pharmaceuticals, Ahmadabad, India (Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus casei, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium breve, Saccharomyces boulardii, Streptococcus thermophilus) | |
| Balance (Protexin Co., Somerset, UK) Lactobacillus strains (L casei, L rhamnosus, L acidophilus, L bulgaricus), Bifidobacterium strains (B breve, B longum), and Streptococcus thermophilus | |
| Lactobacillus plantarum 299v | |
| Unclear | |
| Live Bacillus cereus capsules | |
| Lactobacillus acidophilus |
| Probiotic versus placebo or no intervention | ||||
|---|---|---|---|---|
| No‐recovery | Studies | Participants | Effect estimate Risk ratio [95% CI] | Difference P |
| Type of probiotic | 10 | 574 | — | 0.69 |
| Lactobacillus | 4 | 195 | 0.67 [0.45, 1.00] | — |
| Mixed | 5 | 309 | 0.65 [0.50, 0.83] | — |
| Unclear | 1 | 70 | 0.76 [0.58, 0.98] | — |
| Grade of hepatic encephalopathy | 10 | 574 | — | 0.06 |
| Minimal | 8 | 473 | 0.63 [0.52, 0.76] | — |
| Overt | 2 | 101 | 0.98 [0.64, 1.48] | — |
| Duration of therapy | 10 | 574 | — | 0.43 |
| <= 1 month | 4 | 228 | 0.75 [0.58, 0.96] | — |
| 1 > 2 months | 3 | 117 | 0.65 [0.38, 1.10] | — |
| 2 + months | 3 | 229 | 0.58 [0.43, 0.78] | — |
| Co‐interventions | 10 | 574 | — | 0.17 |
| No treatment | 8 | 473 | 0.63 [0.52, 0.76] | — |
| Bioactive fermentable fibre | 1 | 40 | 1.00 [0.54, 1.86] | — |
| Lactulose | 1 | 61 | 0.96 [0.55, 1.69] | — |
| Plasma ammonia concentration | Studies | Participants | Effect estimate Mean difference [95% CI] | Difference P |
| Type of probiotic | 10 | 580 | — | 0.35 |
| Bifidobacterium | 1 | 125 | ‐9.35 [‐16.09, ‐2.61] | — |
| Lactobacillus | 3 | 121 | ‐11.90 [‐24.41, 0.60] | — |
| Mixed | 4 | 190 | ‐1.80 [‐9.65, 6.06] | — |
| Unclear | 2 | 144 | ‐17.02 [‐44.07, 10.02] | — |
| Grade of hepatic encephalopathy | 10 | 580 | — | 0.85 |
| Minimal | 9 | 455 | ‐8.50 [‐14.38, ‐2.62] | — |
| Overt | 1 | 125 | ‐9.35 [‐16.09, ‐2.61] | — |
| Duration of therapy | 10 | 580 | — | 0.58 |
| <=1 month | 4 | 232 | ‐5.93 [‐12.25, 0.39] | — |
| 1 > 2 months | 4 | 211 | ‐5.11 [‐14.56, 4.34] | — |
| 2 + months | 2 | 137 | ‐18.53 [‐42.32, 5.26] | — |
| Co‐interventions used | 10 | 580 | — | 0.11 |
| No treatment | 7 | 354 | ‐10.42 [‐18.68, ‐2.17] | — |
| Bioactive fermentable fibre | 1 | 40 | ‐2.90 [‐5.51, ‐0.29] | — |
| Lactulose | 2 | 186 | ‐7.88 [‐14.29, ‐1.47] | — |
| Probiotic versus lactulose | ||||
| Plasma ammonia concentration | Studies | Participants | Effect estimate Mean difference [95% CI] | Difference P |
| Type of probiotic | 6 | 325 | — | 0.13 |
| Enterococcus SF68 | 2 | 56 | ‐12.83 [‐24.51, ‐1.15] | — |
| Mixed | 2 | 139 | 1.34 [‐1.72, 4.40] | — |
| Lactobacillus | 1 | 50 | ‐3.17 [‐17.17, 10.83] | — |
| Unclear | 1 | 80 | 1.31 [‐5.70, 8.32] | — |
| Grade of hepatic encephalopathy | 6 | 325 | — | 0.02 |
| Minimal | 4 | 269 | 1.16 [‐1.59, 3.91] | — |
| Overt | 2 | 56 | ‐12.83 [‐24.51, ‐1.15] | — |
| CI: confidence interval | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 All‐cause mortality Show forest plot | 7 | 404 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.23, 1.44] |
| 1.1.1 2 weeks | 1 | 46 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 1.1.2 1 month | 1 | 80 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.01, 7.95] |
| 1.1.3 2 months | 3 | 117 | Risk Ratio (M‐H, Random, 95% CI) | 0.72 [0.11, 4.66] |
| 1.1.4 3 months | 2 | 161 | Risk Ratio (M‐H, Random, 95% CI) | 0.57 [0.19, 1.74] |
| 1.2 No recovery (incomplete resolution of clinical symptoms) Show forest plot | 10 | 574 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.56, 0.79] |
| 1.2.1 1 month | 4 | 228 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.58, 0.96] |
| 1.2.2 2 months | 3 | 117 | Risk Ratio (M‐H, Random, 95% CI) | 0.65 [0.38, 1.10] |
| 1.2.3 3 months | 3 | 229 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.43, 0.78] |
| 1.3 Adverse events Show forest plot | 11 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.3.1 Overt hepatic encephalopathy | 10 | 585 | Risk Ratio (M‐H, Random, 95% CI) | 0.29 [0.16, 0.51] |
| 1.3.2 Infection | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 1.3.3 Hospitalisation | 3 | 163 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.11, 4.00] |
| 1.3.4 Intolerance leading to discontinuation | 1 | 37 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 1.3.5 Change of/or withdrawal from treatment | 9 | 551 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.46, 1.07] |
| 1.4 Quality of life Show forest plot | 3 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.4.1 SF‐36 Physical | 1 | 20 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐5.47, 5.47] |
| 1.4.2 SF‐36 Mental | 1 | 20 | Mean Difference (IV, Random, 95% CI) | ‐4.00 [‐9.82, 1.82] |
| 1.4.3 Change in Total SIP Score | 2 | 95 | Mean Difference (IV, Random, 95% CI) | ‐3.66 [‐7.75, 0.44] |
| 1.4.4 Change in SIP Psychological Score | 2 | 95 | Mean Difference (IV, Random, 95% CI) | ‐3.54 [‐4.95, ‐2.12] |
| 1.4.5 Change in SIP Physical Score | 2 | 95 | Mean Difference (IV, Random, 95% CI) | ‐2.94 [‐4.44, ‐1.44] |
| 1.5 Plasma ammonia concentration (final and change scores) (μmol/L) Show forest plot | 10 | 705 | Mean Difference (IV, Random, 95% CI) | ‐8.29 [‐13.17, ‐3.41] |
| 1.5.1 1 month | 5 | 357 | Mean Difference (IV, Random, 95% CI) | ‐5.55 [‐10.67, ‐0.42] |
| 1.5.2 2 months | 4 | 211 | Mean Difference (IV, Random, 95% CI) | ‐5.11 [‐14.56, 4.34] |
| 1.5.3 3 months | 1 | 73 | Mean Difference (IV, Random, 95% CI) | ‐6.79 [‐10.39, ‐3.19] |
| 1.5.4 6 months | 1 | 64 | Mean Difference (IV, Random, 95% CI) | ‐31.08 [‐40.50, ‐21.66] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 All‐cause mortality Show forest plot | 2 | 200 | Risk Ratio (M‐H, Random, 95% CI) | 5.00 [0.25, 102.00] |
| 2.1.1 1 month | 1 | 80 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 2.1.2 2 months | 1 | 120 | Risk Ratio (M‐H, Random, 95% CI) | 5.00 [0.25, 102.00] |
| 2.2 No recovery (incomplete resolution of clinical symptoms) Show forest plot | 7 | 430 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.85, 1.21] |
| 2.2.1 1 month or less | 5 | 255 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.75, 1.20] |
| 2.2.2 2 months | 1 | 95 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.65, 1.47] |
| 2.2.3 3 months | 1 | 80 | Risk Ratio (M‐H, Random, 95% CI) | 1.24 [0.85, 1.80] |
| 2.3 Adverse events Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.3.1 Overt hepatic encephalopathy | 6 | 420 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [0.63, 2.17] |
| 2.3.2 Infection | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | Not estimable |
| 2.3.3 Hospitalisation | 1 | 80 | Risk Ratio (M‐H, Random, 95% CI) | 0.33 [0.04, 3.07] |
| 2.3.4 Intolerance leading to discontinuation | 3 | 220 | Risk Ratio (M‐H, Random, 95% CI) | 0.35 [0.08, 1.43] |
| 2.3.5 Change of/or withdrawal from treatment | 7 | 490 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.88, 1.82] |
| 2.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 2.4.1 Change in Total SIP Score | 1 | 69 | Mean Difference (IV, Random, 95% CI) | 0.65 [‐1.13, 2.43] |
| 2.4.2 Change in SIP Psychological Score | 1 | 69 | Mean Difference (IV, Random, 95% CI) | 0.48 [‐1.04, 2.00] |
| 2.4.3 Change in SIP Physical Score | 1 | 69 | Mean Difference (IV, Random, 95% CI) | 0.38 [‐0.61, 1.37] |
| 2.5 Plasma ammonia concentration (final and change scores) (μmol/L) Show forest plot | 6 | 325 | Mean Difference (IV, Random, 95% CI) | ‐2.93 [‐9.36, 3.50] |
| 2.5.1 1 month or less | 5 | 248 | Mean Difference (IV, Random, 95% CI) | ‐4.30 [‐13.17, 4.56] |
| 2.5.2 3 months | 1 | 77 | Mean Difference (IV, Random, 95% CI) | 1.16 [‐1.96, 4.28] |
