Management of an episode of acute hepatic encephalopathy

National Guideline Centre (UK)

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National Guideline Centre (UK). Cirrhosis in Over 16s: Assessment and Management. London: National Institute for Health and Care Excellence (NICE); 2016 Jul. (NICE Guideline, No. 50.)

Cirrhosis in Over 16s: Assessment and Management.

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15Management of an episode of acute hepatic encephalopathy

15.1. Introduction

Hepatic encephalopathy is a brain dysfunction caused by liver impairment or portosystemic shunting; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subtle changes in cognition to clinically obvious changes in intellect, behaviour, motor function and consciousness.⁶⁰ It is a debilitating complication of cirrhosis, severely affecting the lives of patients and their carers. It is the commonest complication of cirrhosis and the risk for the first episode of hepatic encephalopathy is 5–25% within 5 years after the diagnosis of cirrhosis and is greatest in those with decompensated liver disease.¹⁸

The diagnosis requires the detection of clinical signs and symptoms suggestive of hepatic encephalopathy in a person with cirrhosis or portosystemic shunting, who does not have an alternative cause of brain dysfunction. Clinically apparent or overt hepatic encephalopathy may arise over a period of hours or days in someone who has previously been stable. Such an episode of acute hepatic encephalopathy may be precipitated by a number of diverse events, such as infection, gastrointestinal haemorrhage, electrolyte disturbance, alcohol misuse or constipation, although in 50% of instances no obvious cause is identified.²¹⁶

It is considered that hepatic encephalopathy is reversible with treatment. At present, therapy for an episode of acute hepatic encephalopathy is directed at the precipitating cause, as well as reducing the production and absorption of gut-derived neurotoxins, particularly ammonia, mainly through bowel cleansing, and the use of non-absorbable disaccharides, such as lactulose. However, there are no universally accepted standards for the treatment of an episode of acute hepatic encephalopathy and consequently, clinical practice is often dictated by local guidelines and personal preferences.

Since there is an unmet need for national recommendations, the GDG decided to compare the clinical and cost- effectiveness of treatments for an episode of acute hepatic encephalopathy in people with cirrhosis. The management of hepatic encephalopathy resulting from acute liver failure or portosystemic shunting, the treatment of minimal hepatic encephalopathy, the treatment of persistent hepatic encephalopathy, and prophylaxis to prevent recurrent hepatic encephalopathy are not included in this review.

For guidance on the prevention of recurrence of episodes of overt hepatic encephalopathy see Rifaximin for preventing episodes of overt hepatic encephalopathy (NICE TA337).

15.2. Review question: What is the most clinically and cost-effective intervention for the first-line treatment of an episode of acute hepatic encephalopathy in people with cirrhosis?

For full details see review protocol in Appendix C.

Table 93

PICO characteristics of review question.

15.3. Clinical evidence

We searched for randomised controlled trials comparing the effectiveness of current therapies or combinations of therapies for an episode of acute hepatic encephalopathy, either against each other or placebo. Twenty-one randomised controlled trials (23 papers) were included in the review;⁵^,⁷^,³³^,³⁴^,⁷¹^,⁹⁵^,⁹⁷^,¹¹⁵^,¹²⁶^,¹³³^,¹⁵⁶^,¹⁶⁹^,¹⁷⁶^-¹⁷⁸^,¹⁹⁹^,²¹⁷^,²¹⁸^,²²⁰^,²³⁶^,²³⁷^,²⁴⁰^,²⁴¹ these are summarised in Table 94.

Table 94

Summary of studies included in the review.

The review population for this question was people with cirrhosis with an episode of acute hepatic encephalopathy. Studies including people with minimal or chronic hepatic encephalopathy were excluded from the review. The review only included treatment of the acute event and studies looking at primary or secondary prophylaxis of hepatic encephalopathy were excluded. A variety of mono and/or combined therapies were used; the evidence is presented separately for each comparison. A network meta-analysis (NMA) was not performed due to an incomplete network with no closed loops, and the variation in how the critical outcome of ‘no improvement in hepatic encephalopathy’ was reported across studies. Evidence from these studies is summarised in the clinical evidence summary tables below (Table 95, Table 96, Table 97, Table 98, Table 99, Table 100, Table 101, Table 102, Table 103, Table 104, Table 105, Table 106, Table 107, Table 108, Table 109, Table 110, Table 111).

See also the study selection flow chart in Appendix E, study evidence tables in Appendix H, forest plots in Appendix K, GRADE tables in Appendix J and excluded studies list in Appendix L.

15.3.1. Non-absorbable disaccharides versus single therapy

Table 95

Clinical evidence summary: non-absorbable disaccharides versus neomycin.

Table 96

Clinical evidence summary: non-absorbable disaccharides versus Rifaximin.

Table 97

Clinical evidence summary: non-absorbable disaccharides versus BCAA.

Table 98

Clinical evidence summary: non-absorbable disaccharides versus PEG 3350.

Table 100

Clinical evidence summary: non-absorbable disaccharides versus sodium benzoate.

15.3.2. Combination therapy (1 intervention + non-absorbable disaccharides) versus non-absorbable disaccharides

Table 101

Clinical evidence summary: Rifaximin + non-absorbable disaccharides versus non-absorbable disaccharides.

Table 102

Clinical evidence summary: BCAA + non-absorbable disaccharides versus non-absorbable disaccharides.

Table 103

Clinical evidence summary: Flumazenil + non-absorbable disaccharides versus non-absorbable disaccharides.

15.3.3. Combination therapy (2 interventions + non-absorbable disaccharides) versus combination therapy (1 intervention + non-absorbable disaccharides)

Table 104

Clinical evidence summary: Flumazenil + BCAA + non-absorbable disaccharides versus BCAA + non-absorbable disaccharides.

Table 105

Clinical evidence summary: LOLA + metronidazole + non-absorbable disaccharides versus metronidazole + non-absorbable disaccharides.

Narrative findings

LOLA + lactulose + metronidazole versus placebo + lactulose + metronidazole

Abid 2011⁵ report that the median duration of hospitalisation following treatment with LOLA was 96 hours (range 48–574) compared to placebo which was 96 hours ([range 90–240] p=0.025).

15.3.4. Single therapy versus placebo

Table 106. Clinical evidence summary: non-absorbable disaccharides versus placebo.

15.3.5. Single therapy versus single therapy

Table 109

Clinical evidence summary: BCAA versus neomycin.

15.3.6. Combination therapy (one intervention + non-absorbable disaccharides) versus single therapy

Table 110

Clinical evidence summary: BCAA + non-absorbable disaccharides versus BCAA.

15.3.7. MARS versus standard medical therapy

Table 111

Clinical evidence summary: MARS versus standard medical therapy.

15.4. Economic evidence

15.4.1. Published literature

No relevant economic evaluations were identified.

See also the economic article selection flow chart in Appendix F.

15.4.2. Unit costs

See Table 99 in Appendix O.

Table 99

Clinical evidence summary: non-absorbable disaccharides versus probiotics.

15.5. Evidence statements

15.5.1. Clinical

Single therapy versus placebo

A clinical benefit was found for non-absorbable disaccharides over placebo for mortality (1 study, 15 patients, Low quality) and therapeutic response (1 study, 15 patients, Very Low quality).
A clinical harm was found for BCAA over placebo for mortality (1 study, 50 patients, Low quality). No difference was found for positive response to treatment (1 study, 42 patients, Very Low quality).
Neomycin (+ BCAA in grades III and IV) showed clinical benefit over placebo (+ BCAA in grades III and IV) for the outcome time until regression to grade 0 hepatic encephalopathy (1 study, 39 patients, Low quality), but no clinical difference for mortality (1 study, 39 patients, Very Low quality).

Single therapy versus single therapy

BCAA showed clinical benefit over neomycin for the outcomes mortality (3 studies, 129 patients, Very Low quality), full improvement to grade 0 hepatic encephalopathy (1 study, 17 patients, Very Low quality), improvement to grade 0 or 1 hepatic encephalopathy (1 study, 17 patients, Low quality) and time to recovery (1 study, 28 patients, Moderate quality).

Non-absorbable disaccharides versus single therapy

Non-absorbable disaccharides showed clinical harm over neomycin for the outcomes mortality and clinical-biochemical improvement (1 study, 18 patients, Low to Very Low quality). No difference was found for side effects (1 study, 18 patients, Moderate quality).
Non-absorbable disaccharides showed clinical harm over rifaximin for mortality (1 study, 103 patients, Low quality). No difference was found for the outcomes unchanged/failure (1 study, 103 patients, Low quality), improvement in hepatic encephalopathy grade (1 study, 54 patients, Low quality), improvement in hepatic encephalopathy index (1 study, 54 patients, Low quality) and adverse events (2 studies, 157 patients, Very Low quality).
Non-absorbable disaccharides showed clinical harm over BCAA for mortality (1 study, 34 patients, Low quality), and complete mental recovery (2 studies, 66 patients, Moderate quality). There was no clinically important difference for the outcome time of arousal (1 study, 34 patients, Moderate quality).
Non-absorbable disaccharides showed clinical harm over PEG 3350 for the outcomes mortality (1 study, 50 patients, Low quality), hepatic encephalopathy resolution (1 study, 48 patients, Low quality), improvement of 1 or more in hepatic encephalopathy grade (1 study, 48 patients, Low quality), length of hospital stay (1 study, 50 patients, Low quality), and adverse events (1 study, 50 patients, Low quality).
Non-absorbable disaccharides showed clinical harm over probiotics for adverse events (1 study, 31 patients, Very Low quality). No difference was found for improvement in hepatic encephalopathy symptoms (1 study, 38 patients, Very Low quality).
No clinical difference was found for non-absorbable disaccharides compared to sodium benzoate for the outcomes mortality (1 study, 74 patients, Low quality), complete response (1 study, 74 patients, Moderate quality), and complications during treatment (1 study, 74 patients, High quality).

Combination therapy (one intervention + non-absorbable disaccharides) versus non-absorbable disaccharides

A clinical benefit was found for rifaximin and non-absorbable disaccharides over non-absorbable disaccharides alone for the outcomes mortality, complete reversal of hepatic encephalopathy and length of hospital stay (1 study, 120 patients, Moderate quality). No difference was found for the outcome side effects related to study medication (1 study, 120 patients, Low quality).
A clinical benefit was found for BCAA and non-absorbable disaccharides over non-absorbable disaccharides alone for the outcomes ‘wake up’ (2 studies, 97 patients, Very Low quality) and treatment failures other than death (1 study, 65 patients, Low quality). For the outcome mortality no difference was found (1 study, 65 patients, Low quality).
A clinical benefit was found for flumazenil and non-absorbable disaccharides over non-absorbable disaccharides alone for the outcomes mortality (1 study, 49 patients, Very Low quality) and clinically relevant response (1 study, 49 patients, Low quality). Clinical harm for the combination with flumazenil was found for adverse events (1 study, 49 patients, Very Low quality).

Combination therapy (2 interventions + non-absorbable disaccharides) versus combination therapy (one intervention + non-absorbable disaccharides)

A clinical benefit was found for flumazenil combined with BCAA and non-absorbable disaccharides over BCAA and non-absorbable disaccharides for the outcome improvement in neurological status (1 study, 54 patients, Very Low quality). No difference was found for the outcomes mortality (1 study, 54 patients, Very Low quality) and side effects (1 study, 54 patients, Low quality).
A clinical benefit was found for LOLA combined with metronidazole and non-absorbable disaccharides over metronidazole and non-absorbable disaccharides for the outcome mortality (2 studies, 200 patients, Very Low quality), improvement of 2 grades from baseline (1 study, 108 patients, High quality) and achievement of hepatic encephalopathy grade 0 (1 study, 80 patients, Very Low quality). A clinical harm was found for the treatment combination involving LOLA for the outcome adverse events (2 studies, 200 patients, Very Low quality).

Combination therapy (1 intervention + non-absorbable disaccharides) versus single therapy

A clinical benefit of BCAA combined with non-absorbable disaccharides over BCAA alone was found for the outcome ‘came out of a coma’ (1 study, 32 patients, Very Low quality).

MARS versus standard medical therapy

A clinical benefit was found for MARS over standard medical therapy for mortality (1 study, 70 patients, Low quality) and responder (1 study, 69 patients, Low quality). A clinical harm was found for MARS for the outcome serious adverse events (1 study, 70 patients, Moderate quality).

15.5.2. Economic

No relevant economic evaluations were identified.

15.6. Recommendations and link to evidence

Recommendations	No recommendation.
Research recommendation	6. In people with cirrhosis and an acute episode of hepatic encephalopathy secondary to a clearly identified, potentially reversible precipitating factor, does management of the precipitating event alone improve the hepatic encephalopathy without specific treatment?
Relative values of different outcomes	The GDG selected the outcomes of mortality, improvement in hepatic encephalopathy and health-related quality of life as critical outcomes, and time to discharge from hospital and treatment-related adverse events as important outcomes for this question. The GDG felt that the length of hospital stay was a useful surrogate marker of improvement in hepatic encephalopathy and was important in assessing the effectiveness of the interventions.
Trade-off between clinical benefits and harms	The GDG noted that the following interventions appeared to show some clinical benefit over non-absorbable disaccharides for at least one outcome: neomycin, rifaximin (for the outcome of mortality only), BCAA, PEG3350 and probiotics (for the outcome of adverse events). However, another study showed no clinical benefit of BCAA over placebo for the outcomes of mortality and positive response of hepatic encephalopathy to treatment. Sodium benzoate showed no clinical benefit over non-absorbable disaccharides. Despite the evidence of clinical effectiveness for some of the interventions compared with non-absorbable disaccharides, the GDG could not discount the Low or Very Low quality of the majority of this evidence. Therefore, the GDG could not be confident that these effect estimates represented the true effect of the interventions. The GDG noted that the evidence for rifaximin versus non-absorbable disaccharides was only available from one study with a high overall mortality rate, conducted in a population which differs considerably from most UK patients with cirrhosis (that is, age and severity). It was agreed that this study was not applicable to a UK population. Rifaximin and BCAAs showed a clinical benefit in combination with non-absorbable disaccharides versus non-absorbable disaccharides alone. The evidence for rifaximin plus non-absorbable disaccharides was of Moderate quality. However, again, evidence was only available from 1 study. The GDG noted the lack of placebo controlled comparisons to assess the effectiveness of individual or combinations of interventions versus treatment of the precipitating cause of the episode of acute hepatic encephalopathy event alone (in the placebo group). Only one study assessed non-absorbable disaccharides (lactitol enemas) versus placebo (tap water enemas) which suggested a clinical benefit of non-absorbable disaccharides. However, the water enema arm of the trial was stopped by the regulator as the mortality rate after the enrolment of the first 5 patients was unacceptably high. Therefore the trial only consisted of 5 people in the placebo arm and 10 people in the lactitol arm. Overall the evidence was Very low or Low quality. In addition, no details were given about the treatment of the precipitating cause of hepatic encephalopathy in either arm. The GDG also noted the improvements in general and intensive care that would have occurred and that there were no trials where the effects of treatment of the precipitating factor alone on the outcome of hepatic encephalopathy had been examined. The GDG considered that the current standard treatment of an episode of acute hepatic encephalopathy is directed at reducing the production and absorption of gut-derived neurotoxins, particularly ammonia, mainly through bowel cleansing, and the use of non-absorbable disaccharides, such as lactulose. This treatment is inexpensive and has a low adverse risk profile but there was no evidence in the review to indicate its superiority over other treatment approaches. Neomycin, although classified as a non-absorbable antibiotic, is absorbed in small quantities and can cause both nephrotoxicity and non-reversible ototoxicity. Although it is inexpensive and has been used in the short-term to treat hepatic encephalopathy when the response to non-absorbable disaccharides is incomplete, the GDG agreed that they would not recommend neomycin based on the limited evidence available. The GDG discussed the possibility that routine use of rifaximin may be associated with antibiotic resistance but felt that insufficient data were available on this subject. Rifaxamin is currently recommended in the UK by NICE TA337 for the treatment of recurrent episodic hepatic encephalopathy in conjunction with a non-absorbable disaccharide. The GDG did not think there was enough evidence of clinical effectiveness in an episode of acute hepatic encephalopathy trials to warrant an off-licence recommendation. The GDG were concerned about the practicality of PEG3350 administration; as a preparation made to a total volume of 4 litres it may not be practical to administer to people with grade 3 or 4 hepatic encephalopathy, nor wise in individuals who may also have fluid retention. Its patient acceptability is likely to be low. It was noted that PEG3350 is not licensed for use in an episode of acute hepatic encephalopathy. The GDG felt that due to the half-life of intravenous flumazenil (40–80 minutes), and the risk of precipitating seizures and arrhythmias, the risks of this treatment would outweigh any potential benefit. This intervention is rarely given in this situation and would require IV administration every few hours as the intervention cannot be given as an infusion. The GDG would not consider recommending flumazenil due to the lack of evidence and these concerns. The GDG discussed that sodium benzoate is not used to treat episodes of acute hepatic encephalopathy in the UK except rarely in specific instances in tertiary care. The GDG would not consider recommending this intervention as the current evidence did not indicate any clinical benefit over non-absorbable disaccharides. LOLA is used occasionally in the UK to treat an episode of acute hepatic encephalopathy however its availability outside tertiary care and specialist centres is limited. The evidence suggested a clinical benefit of LOLA when combined with metronidazole and non-absorbable disaccharides, but the GDG agreed that further research is needed to assess the benefits and harms. Metronidazole is an antibiotic that has a number of adverse effects including dizziness, eye problems and peripheral neuritis. The GDG did not feel that it should be used for this indication. The GDG felt that MARS is an intensive care intervention and should not be used to treat an episode of acute hepatic encephalopathy. The GDG discussed that there is currently variation in the treatment of an acute hepatic encephalopathy episode on a national level. The GDG agreed this is an important area and a recommendation is needed to standardise practice. However, the evidence for each comparison was sparse and the evidence was of Low or Very Low quality. The lack of High quality evidence was not necessarily a lack of effect of any of the interventions, but the GDG agreed there was insufficient evidence to make a recommendation. The GDG thought that further research is needed and have made a future research recommendation. They discussed that the most commonly used intervention currently is lactulose, and that this current practice should continue until further research is carried out. The GDG noted the lack of High quality evidence from placebo controlled trials in this area, perhaps because it would be unethical not to give an intervention to someone in this clinical situation. However, they all agreed that the identification and treatment of the precipitant of the episode of acute hepatic encephalopathy may account for a proportion of the clinical benefit observed in practice. The GDG also noted that many of the studies were old and treatments of the precipitating cause of an episode of acute hepatic encephalopathy event will have changed considerably since they were published. The GDG agreed that evidence is needed to show effectiveness of current interventions before they could consider head-to-head comparisons and comparisons of different combinations. Thus, it considered that in people with cirrhosis experiencing an episode of acute hepatic encephalopathy with a clear, well-defined precipitating factor it would be reasonable to investigate whether treatment of the precipitating factor alone would be effective in ameliorating the hepatic encephalopathy. This would be done by randomising participants to treatment of the precipitant factor alone or with the addition of lactulose. If it were shown that treatment with lactulose provided additional benefit then the comparative efficacy and safety of other agents such as rifaximin, LOLA or BCAA could be explored.
Trade-off between net clinical effects and costs	No relevant published economic evidence was identified. The GDG considered the standard UK costs of the alternative interventions, but as the GDG decided that there was insufficient clinical evidence to recommend an intervention, that decision was not taken on economic grounds.
Quality of evidence	The GDG noted that the studies included in the evidence base spanned a 33-year period and that many studies were over 15 years old. The most recent study was from 2014. The majority of the evidence found was of Low to Very Low quality. The GDG noted that this may be due to a lack of evidence (with evidence only available from small RCTs for the majority of comparisons), rather than a lack of effect. The GDG also noted that the lack of High quality evidence of any treatment versus placebo made the head-to-head comparisons of single or combination therapy more difficult to interpret. A number of results did have Moderate quality evidence and the GDG noted these when considering a recommendation. When considering the results of individual studies, the GDG noted that many of the studies were conducted more than 15 years ago and some much longer than this. The GDG felt that the standard of care for the management of acute hepatic encephalopathy (particularly intensive care support) would be significantly better now than in the 1980s and 1990s.
Other considerations	A number of studies of rifaximin were excluded because they were looking at the treatment of chronic or minimal hepatic encephalopathy, or the prophylaxis of hepatic encephalopathy. Research recommendation Hepatic encephalopathy is a major complication of cirrhosis. Approximately 50% of people with cirrhosis will develop clinically apparent hepatic encephalopathy at some stage after diagnosis – the risk being around 5–25% within 5 years. Hospital admissions are common and inpatient stays often prolonged. The presence of hepatic encephalopathy is associated with a significant increase in mortality; survival after the first episode is 42% at 1 year and 23% at 3 years. At present, treatment of the hepatic encephalopathy is directed primarily at reducing the production and absorption of gut-derived neurotoxins, particularly ammonia, mainly through bowel cleansing, and the use of non-absorbable disaccharides, such as lactulose, although several other agents such as non-absorbable antibiotics are also used. However, in approximately 50% of people admitted with episodic hepatic encephalopathy there is a clearly defined precipitating factor (for example, infections, gastrointestinal bleeding or overuse of diuretics). Treatment is often challenging and some people may need to be cared for in an intensive care setting, at least initially. The identification and correction of any precipitating events is important as there is evidence that this alone may improve hepatic encephalopathy without recourse to specific therapies. However, this has not been rigorously tested in a randomised clinical trial.

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