Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

all patients

1st line – supportive care + reversal of precipitating factors + investigation of alternative causes of altered mental status

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ACUTE
|
all patients
1st line – 

supportive care + reversal of precipitating factors + investigation of alternative causes of altered mental status

Supportive care involves frequently monitoring the patient's neurological and mental status. Comatose patients should be admitted to intensive care and their airway protected to avoid aspiration. Intracranial pressure monitoring may be needed for patients with significant intracerebral oedema.

If precipitating factors have been identified through the history and physical examination, these need to be corrected. Precipitating factors include hypovolaemia, gastrointestinal bleeding, infections, electrolyte disturbances (hypokalaemia, hyponatraemia) and renal failure, sedative or opioid ingestion, diuretic overdose, hypoxia, hypoglycaemia, excessive dietary protein intake, constipation, acute hepatic or portal vein thrombosis, and recent placement of a transjugular intra-hepatic portosystemic shunt (TIPS).[1][16][17][18][19] Occasionally TIPS must be occluded if the condition cannot otherwise be managed. Rapid resolution of constipation and rapid removal of blood from the gastrointestinal tract in the setting of a gastrointestinal bleed has been shown to improve recovery from an episode of HE.[2] Demonstrated or suspected vitamin or micronutrient deficiencies should be treated as they can compound HE. Patients with cirrhosis of any aetiology are prone to deficiencies in water-soluble vitamins, especially thiamine.[2]

Patients may require a short-term protein-restricted diet after HE is diagnosed but should not continue protein restriction indefinitely, because malnutrition and sarcopenia are risk factors for HE. The recommended daily protein intake is 1.2 to 1.5 g/kg/day.[1]

Patients with cirrhosis are also prone to altered mental status due to other causes, including medications (e.g., opioids, benzodiazepines, and proton-pump inhibitors), infections, altered electrolytes, alcohol, illicit drugs, and strokes. It is important to exclude these alternative or synergistic causes before assuming that all mental statue alteration in patients with cirrhosis is HE.[19]

Plus – lactulose

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ACUTE
|
all patients
Plus – 

lactulose

Treatment recommended for ALL patients in selected patient group

Lactulose is recommended first line for the management of episodic overt HE.[1][2]

Meta-analysis suggests a beneficial effect of non-absorbable disaccharides (lactulose, lactitol) on mortality compared with placebo or no intervention.[29] [ Cochrane Clinical Answers logo ] [Evidence B]

Rectal enema may be used if the patient is in coma or impending coma. The patient should be switched to oral therapy as soon as possible.

Primary options

lactulose: 20-30 g (30-45 mL) orally every 1-2 hours until laxative effect, then titrate dose to produce 2-3 loose stools per day; 300 mL diluted with 700 mL water and given as rectal enema, retain for 30-60 minutes, may be repeated every 4-6 hours

2nd line – supportive care + reversal of precipitating factors + investigation of alternative causes of altered mental status

Back
ACUTE
|
all patients
2nd line – 

supportive care + reversal of precipitating factors + investigation of alternative causes of altered mental status

Supportive care involves frequently monitoring the patient's neurological and mental status. Comatose patients should be admitted to intensive care and their airway protected to avoid aspiration. Intracranial pressure monitoring may be needed for patients with significant intracerebral oedema.

If precipitating factors have been identified through the history and physical examination, these need to be corrected. Precipitating factors include hypovolaemia, gastrointestinal bleeding, infections, electrolyte disturbances (hypokalaemia, hyponatraemia) and renal failure, sedative or opioid ingestion, diuretic overdose, hypoxia, hypoglycaemia, excessive dietary protein intake, constipation, acute hepatic or portal vein thrombosis, and recent placement of a transjugular intra-hepatic portosystemic shunt (TIPS).[1][16][17][18][19] Occasionally TIPS must be occluded if the condition cannot otherwise be managed. Rapid resolution of constipation and rapid removal of blood from the gastrointestinal tract in the setting of a gastrointestinal bleed (using lactulose or mannitol via nasogastric tube, or with lactulose enemas) has been shown to improve recovery from an episode of HE.[2] Demonstrated or suspected vitamin or micronutrient deficiencies should be treated as they can compound HE. Patients with cirrhosis of any aetiology are prone to deficiencies in water-soluble vitamins, especially thiamine.[2]

Patients may require a short-term protein-restricted diet after HE is diagnosed but should not continue protein restriction indefinitely, because malnutrition and sarcopenia are risk factors for HE. The recommended daily protein intake is 1.2 to 1.5 g/kg/day.[1]

Patients with cirrhosis are also prone to altered mental status due to other causes, including medications (e.g., opioids, benzodiazepines, and proton-pump inhibitors), infections, altered electrolytes, alcohol, illicit drugs, and strokes. It is important to exclude these alternative or synergistic causes before assuming that all mental statue alteration in patients with cirrhosis is HE.[19]

Plus – rifaximin ± lactulose

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ACUTE
|
all patients
Plus – 

rifaximin ± lactulose

Treatment recommended for ALL patients in selected patient group

Rifaximin should be considered in patients with persistent symptoms despite treatment with lactulose or those who cannot tolerate lactulose.[31] It is recommended as add-on therapy for episodic overt HE.[1] Rifaximin is typically added to, rather than substituted for, lactulose.

One systematic review and meta-analysis reported that rifaximin has a beneficial effect on mortality and full recovery from HE compared with placebo, non-absorbable disaccharides, or other antibiotics.[32] Another meta-analysis found that the addition of rifaximin to lactulose decreases mortality and improves clinical efficacy compared with lactulose alone.[33]

Rifaximin is usually better tolerated than lactulose.[34]

Rectal enema of lactulose may be used if the patient is in coma or impending coma. The patient should be switched to oral therapy as soon as possible.

Primary options

rifaximin: 550 mg orally twice daily

OR

rifaximin: 550 mg orally twice daily

and

lactulose: 20-30 g (30-45 mL) orally every 1-2 hours until laxative effect, then titrate dose to produce 2-3 loose stools per day; 300 mL diluted with 700 mL water and given as rectal enema, retain for 30-60 minutes, may be repeated every 4-6 hours

3rd line – supportive care + reversal of precipitating factors + investigation of alternative causes of altered mental status

Back
ACUTE
|
all patients
3rd line – 

supportive care + reversal of precipitating factors + investigation of alternative causes of altered mental status

Supportive care involves frequently monitoring the patient's neurological and mental status. Comatose patients should be admitted to intensive care and their airway protected to avoid aspiration. Intracranial pressure monitoring may be needed for patients with significant intracerebral oedema.

If precipitating factors have been identified through the history and physical examination, these need to be corrected. Precipitating factors include hypovolaemia, gastrointestinal bleeding, infections, electrolyte disturbances (hypokalaemia, hyponatraemia) and renal failure, sedative or opioid ingestion, diuretic overdose, hypoxia, hypoglycaemia, excessive dietary protein intake, constipation, acute hepatic or portal vein thrombosis, and recent placement of a transjugular intra-hepatic portosystemic shunt (TIPS).[1][16][17][18][19] Occasionally TIPS must be occluded if the condition cannot otherwise be managed. Rapid resolution of constipation and rapid removal of blood from the gastrointestinal tract in the setting of a gastrointestinal bleed (using lactulose or mannitol via nasogastric tube, or with lactulose enemas) has been shown to improve recovery from an episode of HE.[2] Demonstrated or suspected vitamin or micronutrient deficiencies should be treated as they can compound HE. Patients with cirrhosis of any aetiology are prone to deficiencies in water-soluble vitamins, especially thiamine.[2]

Patients may require a short-term protein-restricted diet after HE is diagnosed but should not continue protein restriction indefinitely, because malnutrition and sarcopenia are risk factors for HE. The recommended daily protein intake is 1.2 to 1.5 g/kg/day.[1]

Patients with cirrhosis are also prone to altered mental status due to other causes, including medications (e.g., opioids, benzodiazepines, and proton-pump inhibitors), infections, altered electrolytes, alcohol, illicit drugs, and strokes. It is important to exclude these alternative or synergistic causes before assuming that all mental statue alteration in patients with cirrhosis is HE.[19]

Plus – L-ornithine-L-aspartate or branched-chain amino acids

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ACUTE
|
all patients
Plus – 

L-ornithine-L-aspartate or branched-chain amino acids

Treatment recommended for ALL patients in selected patient group

Guidelines advise that intravenous L-ornithine-L-aspartate (LOLA) or branched-chain amino acids (BCAAs) can be used as an alternative agent or an additional agent for patients who do not respond to conventional therapy (lactulose ± rifaximin).[1]

Meta-analyses of randomised controlled trials suggest a possible benefit of LOLA on mortality and neurocognitive manifestations of overt HE compared with placebo or no intervention.[35][36] However, the beneficial effect is uncertain because the quality of evidence is low.[35]

One meta-analysis of 16 studies of BCAAs demonstrated improvement in HE compared with placebo or diet, but with significant side effects of nausea and diarrhoea.[38] All-cause mortality did not differ between BCAAs and controls (including placebo, diet, lactulose, neomycin), but these analyses may have been underpowered.[38] [ Cochrane Clinical Answers logo ]

These agents are not available in the US.

Consider – rifaximin ± lactulose

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ACUTE
|
all patients
Consider – 

rifaximin ± lactulose

Additional treatment recommended for SOME patients in selected patient group

Guidelines advise that L-ornithine-L-aspartate (LOLA) or branched-chain amino acids (BCAAs) may be used as an additional agent in patients who do not respond to conventional therapy (rifaximin ± lactulose).[1] Whether they are used as an alternative agent on their own, or in combination with existing therapy (rifaximin ± lactulose), depends on clinician choice.

Rectal enema of lactulose may be used if the patient is in coma or impending coma. The patient should be switched to oral therapy as soon as possible.

Primary options

rifaximin: 550 mg orally twice daily

OR

rifaximin: 550 mg orally twice daily

and

lactulose: 20-30 g (30-45 mL) orally every 1-2 hours until laxative effect, then titrate dose to produce 2-3 loose stools per day; 300 mL diluted with 700 mL water and given as rectal enema, retain for 30-60 minutes, may be repeated every 4-6 hours

ONGOING

previous/recurrent episode

1st line – lactulose

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ONGOING
|
previous/recurrent episode
1st line – 

lactulose

Lactulose is recommended as secondary prophylaxis following a first episode of overt HE.[1][2][5] There is no strong evidence to guide the decision as to if, or when, prophylactic treatment for HE should be discontinued. Guidelines recommend that if liver and nutritional status have improved, and precipitating factors have been controlled, discontinuation of HE treatment can be considered on an individual basis.[2]

Patients should be instructed to avoid opioids, alcohol, and benzodiazepines. There is no evidence to support the recommendation to restrict protein intake in patients with HE.

Primary options

lactulose: 20-30 g (30-45 mL) orally every 1-2 hours until laxative effect, then titrate dose to produce 2-3 loose stools per day

Consider – rifaximin

Back
ONGOING
|
previous/recurrent episode
Consider – 

rifaximin

Additional treatment recommended for SOME patients in selected patient group

Rifaximin effectively prevents recurrence of HE and is a recommended add-on therapy to lactulose for secondary prophylaxis following ≥1 episode of overt HE within 6 months of the first one.[2]

In one randomised controlled trial, a 6-month course of rifaximin decreased the risk of relapse and hospitalisation due to HE in patients with recurrent HE.[39] One systematic review and meta-analysis found that rifaximin had a beneficial effect on secondary prevention of HE, full recovery from HE, and mortality.[32] There is no strong evidence to guide the decision as to if, or when, prophylactic treatment for HE should be discontinued. Guidelines recommend that if liver and nutritional status have improved, and precipitating factors have been controlled, discontinuation of HE treatment can be considered on an individual basis.[2]

Primary options

rifaximin: 550 mg orally twice daily

Consider – referral to liver transplant centre

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ONGOING
|
previous/recurrent episode
Consider – 

referral to liver transplant centre

Additional treatment recommended for SOME patients in selected patient group

The development of HE carries a poor prognosis, and appropriate candidates should be referred to liver transplant centres after a first episode of encephalopathy. Those with end-stage liver disease and recurrent or persistent HE not responding to other treatments should be considered for transplantation.[2] The most commonly used prognostic model for estimating disease severity and listing for transplant is the Model for End-stage Liver Disease (MELD) score. A score of >15 is an appropriate indicator for referral for transplant evaluation.[40][41] [ MELDNa scores (for liver transplantation listing purposes, not appropriate for patients under age 12 years) (SI units) Opens in new window ] ​​ The Child-Pugh score can also be used.[2] [ Child Pugh classification for severity of liver disease (SI units) Opens in new window ]

Consider – evaluation for spontaneous portosystemic shunts that could be embolised

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ONGOING
|
previous/recurrent episode
Consider – 

evaluation for spontaneous portosystemic shunts that could be embolised

Additional treatment recommended for SOME patients in selected patient group

Obliteration of accessible portosystemic shunts in patients with cirrhosis with recurrent or persistent HE (despite adequate medical treatment) can be considered in stable patients with a low MELD score (<11) and no obvious contraindications.[2]

Up to one third of patients with cirrhosis have portosystemic shunts on imaging. Large spontaneous shunts may contribute to recurrent or persistent HE. Almost 50% of these are splenorenal shunts.[2]

Only two small retrospective cohort studies including a total of 58 patients have examined the utility of shunt obliteration by embolisation.[42][43] In one European multi-centre cohort study, shunt embolisation in patients with recurrent or persistent HE who were diagnosed with a single large portosystemic shunt resulted in 59% of patients being free of HE at 100 days and 49% remaining free of HE for 2 years. Hospitalisation rate and HE severity were also decreased.[42]

The success and safety of shunt embolization seems to be dependent on whether there is sufficient functional liver mass to accommodate redirected portal flow; hence the recommendation that patients should have a MELD score of <11. In patients with a MELD score of 11 or more, there is an increased risk of de novo development or aggravation of pre-existing varices, portal hypertensive gastropathy, or ascites.[2]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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