CONTENTS

• Rapid Reference 🚀
• Introduction
• Clinical features
• Diagnosis
  • Liver function tests
  • Ammonia
  • EEG
  • Neuroimaging
  • Hepatic encephalopathy vs. EtOH withdrawal
  • Diagnostic approach
• Causes & evaluation of cause
• Treatment
  • Cathartic (lactulose and/or polyethylene glycol)
  • Rifaxamin 
  • Manage triggers & coexisting problems
  • Avoid sedatives like the plague
  • Nutritional support & gut access
  • Treatments of desperation
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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Hepatic Encephalopathy Checklist ✅

evaluation of cause (more)

• Immediate fingerstick glucose.
• Basic labs (liver function tests, electrolytes including Ca/Mg/Phos).
• Paracentesis if ascites present (to exclude SBP).
• CT head if intracranial hemorrhage possible.
• Review medication list.
• Consider basic infection workup (e.g. chest X-ray, urinalysis, possibly blood cultures).
• Consider: Lumbar puncture, MRI, EEG.

empiric therapy for Wernicke encephalopathy (more)

• Thiamine 500 mg IV q8hr.

core therapies (more)

• Cathartic:  One or both of the following:
  • Lactulose:  Start 30 ml q2-4 hr; titrate to >4 bowel movements per day.
  • Polyethylene glycol: 3-4 liters (same preparation as used prior to colonoscopy).
• Rifaximin 550 mg BID (initiate immediately).

avoid any long-acting neuroactive medications (more)

• Review medication list and D/C deliriogenic medications.
• For intubated patient:  Avoid any sedation or analgesia other than propofol or dexmedetomidine.

aggressive treatments for any coexisting problems (more)

• Follow electrolytes and treat abnormalities (especially sodium abnormalities).
• Treat any coexisting renal failure (may include therapy for hepatorenal syndrome).
• Treat any coexisting infection.

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introduction

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types of hepatic encephalopathy

• Type A:  Due to acute liver failure – this is unique and highly morbid situation.📖
• Type B:  Due to portosystemic shunting without any liver disease (rare).
• Type C:  Due to cirrhosis.

what this chapter is about

• This chapter is primarily about type C hepatic encephalopathy (i.e., occuring in the context of chronic cirrhosis).  This must not be confused with encephalopathy due to acute hepatic failure, a more malignant process requiring different treatment.📖
• The chapter is predominantly about severe Type C hepatic encephalopathy – especially causing stupor/coma that requires ICU admission.

overall philosophy for the patient intubated due to severe hepatic encephalopathy

• The overall prognosis of these patients is generally quite poor, unless they are candidates for hepatic transplantation.
  • Discussions regarding prognosis and goals of care should be pursued with the patient's family.
  • Hepatic encephalopathy may be associated with a surprisingly low one-year survival (e.g., 35-45%).(33838857)
• Generally, an organized and aggressive strategy can be successful in waking up the patient sufficiently to extubate.
  • Although the long-term prognosis is usually poor, in the short term these patients can often survive their ICU course.
  • For patients with true hepatic decompensation and acute-on-chronic liver failure, the outlook is worse.

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clinical features of hepatic encephalopathy

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typical presentation:  delirium

• The main finding is a non-focal, metabolic delirium with symptoms ranging from subtle alterations of consciousness to frank coma.
• Overall this may present similarly to other forms of delirium.  However, it tends to cause more of a hypoactive form of delirium (rather than hyperactive delirium).

clues to hepatic encephalopathy as the etiology of delirium

• Asterixis
  • Defined as the inability to maintain a stable posture.  When asked to hold hands outstretched, this generates a “flapping tremor” (video below).
  • Asterixis is the hallmark of hepatic encephalopathy, but also seen in other metabolic derangements (including uremia, hypercapnia, and hypoglycemia).
  • Asterixis be lost in the most severe stages of hepatic encephalopathy (e.g., coma).
  • Hyperreflexia, hypertonia, and clonus may also occur.
• Cirrhosis may lead to respiratory alkalosis due to an increased respiratory drive.  This can be a useful clue to hepatic encephalopathy for a patient intubated due to hypoactive delirium.
• Prior history of hepatic encephalopathy.  As hepatic dysfunction worsens, patients will have recurrent episodes of hepatic encephalopathy.

more severe manifestations

• Stupor/coma delaying extubation is a common manifestation of hepatic encephalopathy in the ICU.  The typical scenario would be a patient who is admitted for a gastrointestinal hemorrhage and intubated to facilitate endoscopy.  When the time comes for extubation, the patient is too stuporous to be extubated.
• Seizures can occur, albeit less frequently.

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liver function tests

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• These will usually be abnormal (reflecting underlying cirrhosis).
• Hepatic encephalopathy can occur with normal liver tests (liver tests aren't tremendously sensitive for cirrhosis).

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ammonia

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general:  use of ammonia in type C hepatic encephalopathy

• The value of ammonia level in hepatic encephalopathy has been debated for decades.  This debate is nearly impossible to resolve, because there is no gold-standard diagnostic test for hepatic encephalopathy.  Consequently, a mismatch between ammonia levels and the clinical diagnosis of hepatic encephalopathy could reflect weakness in one or both of these entities.
• Ammonia is far more useful in acute liver failure (type A hepatic encephalopathy) than cirrhosis (type C hepatic encephalopathy).
• Serum ammonia level has a limited utility in general, but this may be reasonable to obtain in specific patients (while being mindful of the test's limitations).

limitations on the use of ammonia

• Poor overall performance:(25117134, 28786433)
  • Imperfect sensitivity (perhaps ~50-90%, depending on disease severity).  Patients can have hepatic encephalopathy without an elevated ammonia level.
  • Limited specificity (perhaps ~75%).  Cirrhotic patients can have an elevated ammonia, without having clinical encephalopathy.
• Ammonia levels may fluctuate considerably over time (e.g., increasing after a meal).
• Hepatic encephalopathy may result from a synergistic interaction of toxins (e.g., ammonia) plus systemic inflammation.  Thus, the relationship between ammonia and hepatic encephalopathy isn't linear.

potential use of serum ammonia ?

• Ammonia level might be most useful in patients who don't carry a definite diagnosis of cirrhosis (e.g., cirrhosis can occur without obvious abnormality on hepatic ultrasonography or liver function tests).  In this context, an ammonia elevation could support the diagnosis of cirrhosis with hepatic encephalopathy.
• For a patient with obvert confusion, a normal ammonia might imply the need to more aggressively search for an alternative diagnosis.(32618647)
• ⚠️ Ammonia levels can neither rule-in, nor rule-out, hepatic encephalopathy.  The test may be used to color the clinical picture, but it shouldn't be over-relied upon.

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EEG

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EEG is not usually needed in the evaluation or management of hepatic encephalopathy.  

exclusion of seizure

• The primary role is exclusion of seizure.
• Indications may include patients with a history of seizures, or clinical findings concerning for nonconvulsive status epilepticus.

triphasic waves

• Hepatic encephalopathy classically produces a pattern of triphasic waves.
• These are not specific for hepatic encephalopathy (may be seen in other forms of metabolic encephalopathy, or drug intoxication).

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neuroimaging

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CT scan

• The primary role of CT scan is to exclude alternative pathology (especially subdural hematoma).
• Patients with a history of hepatic encephalopathy and/or alcoholism are prone to falls, so there should be a low threshold to obtain a CT scan.
• For patients who develop encephalopathy within the hospital (e.g., following a gastrointestinal hemorrhage), neuroimaging has lower yield.

MRI

• Obtained less often, but may be useful to exclude alternative pathologies (especially among patients who are not responding to therapy for hepatic encephalopathy).
• Hepatic encephalopathy may cause T1 hyperintensity in the basal ganglia, especially the globus pallidus (possibly due to shunting of manganese past the liver).

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hepatic encephalopathy versus alcohol withdrawal

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Occasionally, in a patient with cirrhosis due to alcoholism there will be a question of sorting out hepatic encephalopathy versus alcohol withdrawal.  These are fundamentally nearly opposite pathologies:

Generally, this differentiation can be made on the basis of history and physical examination.  The importance of an accurate drinking history cannot be over-emphasized (many patients will have a history of “alcoholism” in their electronic medical records, despite having stopped drinking.)

Be careful about over-diagnosing patients with alcohol withdrawal, because the treatment for alcohol withdrawal can be disastrous in a patient who actually has hepatic encephalopathy:

• Patients with hepatic encephalopathy have excess GABA stimulation, so they are very sensitive to GABAergic medications (e.g., benzodiazepines or barbiturates).
• Administration of benzodiazepines or barbiturates to a patient with hepatic encephalopathy risks inducing a prolonged comatose state.

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diagnostic approach

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hepatic encephalopathy is a challenging diagnosis for two reasons

• #1:  There is no test which can prove the presence of hepatic encephalopathy.
  • The closest we have to a definitive “test” for hepatic encephalopathy is improvement following therapy – but even this isn't 100% specific.  Many forms of metabolic encephalopathy will improve with supportive care.
• #2:  Hepatic encephalopathy may often coexist with other causes of delirium.
  • As with ICU-acquired delirium, patients with hepatic encephalopathy often have multifactorial delirium.
  • Thus, discovering one cause of delirium (e.g., hyponatremia) doesn't necessarily exclude coexisting hepatic encephalopathy.

general approach

• Patients should be approached with a broad differential diagnosis.📖
• Particular attention should be given to the following differential diagnostic possibilities:
  • Subdural hematoma (may present without localizing findings).
  • Infection (including meningitis or encephalitis).
  • Hypoglycemia.
  • Alcohol intoxication or withdrawal.
  • Wernicke's encephalopathy.
• ⚠️ Ultimately, hepatic encephalopathy is a diagnosis of exclusion.  Beware of anchoring onto the diagnosis of hepatic encephalopathy without excluding other alternatives (especially among patients presenting to the hospital with altered mental status).

empiric therapy

• The treatments for hepatic encephalopathy are fairly benign.
• In situations of diagnostic uncertainty, a reasonable approach is to empirically treat for hepatic encephalopathy (while continuing to evaluate for alternative causes of delirium).

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causes & evaluation of cause

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precipitating factors

• Most common
  • #1 = Infection:
    • Spontaneous bacterial peritonitis.📖
    • Urinary tract infection.
    • Pneumonia.
  • GI bleed.
  • Nonadherence with lactulose or rifaximin (or constipation).
  • Volume depletion (e.g., over-diuresis).
  • Electrolyte abnormalities (especially ⬇️ Na or ⬇️ K).
  • Renal failure (including hepatorenal syndrome).
  • Deliriogenic medications.
• Less common:
  • Transhepatic intravascular portosystemic shunt (TIPS), or spontaneous portosystemic shunts.
  • Hepatic or portal vein thrombosis.

basic evaluation for etiology (appropriate in most patients)

• Basic labs (electrolytes, liver function tests).
• Paracentesis, if substantial ascitic fluid on bedside ultrasonography.
• Chest X-ray.
• Urinalysis and possibly blood cultures.

advanced evaluation for etiology (consider based on context)

• Lumbar puncture (may be challenge in context of coagulopathy).
• MRI of the brain.
• EEG to exclude seizures.
• Right upper-quadrant ultrasonography with Doppler, to exclude hepatic vein or portal vein thrombosis (if acutely deteriorating hepatic function).

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cathartic (lactulose and/or polyethylene glycol)

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lactulose

• Lactulose has traditionally been the cornerstone of therapy for hepatic encephalopathy.
  • Promotes growth of non-ammonia-producing, benign bacteria (e.g., lactobacillus).
  • Lactulose works via numerous potential mechanisms (e.g., lowers the colonic pH which traps ammonia in the gut, laxative agent).
  • Supported by reasonable amount of evidence. (27081787)
• Aggressive dosing is needed, with an ultimate goal of achieving >4 bowel movements per day.
  • If the patient isn't having adequate bowel movements, then lactulose won't work.
  • Start at a high dose and then titrate downwards (e.g., 30 ml Q2hr until frequent bowel movements, then decrease to 30 ml Q6hr and titrate).
  • Typically, an intubated patient will require an orogastric tube and a rectal tube.
• Lactulose enemas
  • Theoretically may be used in a patient without enteral access (one regimen is 300 ml lactulose in 700 ml water twice daily as a retention enema).

polyethylene glycol

• Polyethylene glycol (PEG) is an inert osmotic cathartic agent.  It is widely used to prepare the colon prior to colonoscopy.  When provided in a large volume of water, it induces minimal electrolyte shifts and is very safe. (11246353)
• Recently multiple RCTs found that polyethylene glycol was superior to lactulose, in terms of achieving more rapid resolution of hepatic encephalopathy.(25243839, 30234645)  This finding was substantiated in a meta-analysis of four RCTs.(34006606)  One further study found that the addition of polyethylene glycol to lactulose also accelerated recovery.(28316761)
• Reasons that polyethylene glycol was superior to lactulose may include the following:
  • (1) These studies used a standard pre-colonoscopy regimen of polyethylene glycol (~4 liters).  This will undoubtedly cause more rapid and complete bowel evacuation, compared to standard regimens of lactulose.
  • (2) When diluted in large volumes of water, polyethylene glycol has little effect on electrolyte levels of volume status.  In contrast, aggressive lactulose therapy will cause hypernatremia.
• These studies are small, so it may be premature to conclude that polyethylene glycol is definitively superior to lactulose.  The following conclusions may be reasonable at this point in time:
  • (1) Bowel cleansing with large-volume polyethylene glycol is used widely on patients prior to colonoscopy and is accepted to be extremely safe.
  • (2) Polyethylene glycol is a reasonable and evidence-based approach to treating hepatic encephalopathy that could be superior to lactulose.  If polyethylene glycol is used, it should initially be administered with a large volume of water to avoid electrolyte shifts (e.g., using a standard 3-4 liter commercial preparation as is done prior to colonoscopy).
  • (3) Polyethylene glycol may be used as add-on therapy for a patient who has been started on lactulose and isn't responding adequately.

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rifaxamin

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• Rifaximin is a non-absorable antibiotic which may suppress bacterial overgrowth and ammonia production.💊 Since it is not absorbed, it is extremely safe (with essentially no systemic side-effects).
• For patients who are intubated or severely stuporous, rifaximin should be initiated immediately (in combination with a cathartic agent such as lactulose or polyethylene glycol).  Combination therapy involving rifaximin plus lactulose has been shown to reduce length-of-stay, compared to lactulose monotherapy.(23877348; 24849268)
• The usual dose is 550 mg PO BID.

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manage triggers & coexisting problems

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hyponatremia

• Mild to moderate hyponatremia is often seen upon admission (it's a common problem in the context of cirrhosis).  This may sometimes function as a precipitating cause of hepatic encephalopathy.
• Lactulose alone is generally a very effective treatment for both hyponatremia and also hepatic encephalopathy.🌊
  • Lactulose is an osmotic cathartic agent, so it removes water from the body and increases the sodium concentration.
• More on the treatment of hyponatremia in cirrhosis: 📖.

hypernatremia

• This commonly develops during treatment of hepatic encephalopathy, as a side-effect of lactulose therapy.
• Hypernatremia must be managed aggressively (with enteral water or IV D5W), otherwise it will contribute to the patient's encephalopathy and agitation.📖
• For patient who require ongoing treatment with a cathartic, switching from lactulose to polyethylene glycol may reduce free water losses and thereby facilitate effective treatment of hypernatremia.

hypokalemia

• Hypokalemia may increase ammonium reabsorption by the kidneys, potentially exacerbating hepatic encephalopathy.📖

renal support

• Adequate renal function is essential to allow patients to clear toxins and emerge from encephalopathy.
• Renal function should be supported aggressively (e.g., with avoidance of nephrotoxins or volume depletion).
• If the kidney starts failing, consider aggressive support.📖

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avoid sedating medications like the plague

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avoid sedating medications!

• Patients with hepatic encephalopathy are often exquisitely sensitive to sedating medications (e.g., benzodiazepines, opioids, antipsychotics).
• For an intubated patient with hepatic encephalopathy, it is best to avoid any sedative or analgesic, except agents with extremely short half-lives (e.g., propofol or dexmedetomidine).(19394004)
  • Even small doses of a long-acting sedative may delay extubation.
  • One trick to facilitate extubation is to allow all other sedating medications to wash out of the patient.
  • Patients who are comatose due to hepatic encephalopathy are usually very sensitive to sedation, so they often don't require much propofol to achieve comfort (they are somnolent to begin with – that's their problem).
• For patients with stable cirrhosis, a total of two grams of acetaminophen daily may be used daily for analgesia.
• (If a patient with hepatic encephalopathy can't be rendered comfortable with low-dose propofol, it's probably time for extubation.)

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nutritional support & gut access

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nutritional support

• Intubated patients with hepatic encephalopathy should receive enteral nutrition just like any other intubated patient.
• Recent guidelines don't recommend restricting protein intake among these patients.

empiric thiamine for Wernicke's encephalopathy in alcoholism

• Patients with alcoholism and cirrhosis may be at risk for Wernicke's encephalopathy.
• Differentiation of Wernicke's encephalopathy from hepatic encephalopathy is basically impossible.
  • There are no lab tests capable of doing this promptly.
  • Physical examination signs of Wernicke's encephalopathy (nystagmus, ataxia) may be absent in a comatose patient.
• If there is significant concern for Wernicke's encephalopathy, the safest thing is to treat empirically with thiamine (500 mg IV q8hrs).  IV thiamine is entirely safe.

place a small-bore nasal feeding tube prior to extubation

• Patients will often be unable to take oral medications immediately following extubation due to somnolence.  However, it is essential to continue lactulose and rifaximin therapy without interruption.  Inability to give PO medications following extubation is a potential cause of relapse & reintubation.
• It may be easiest and best-tolerated to place a small-bore nasal feeding tube early in the patient's course, while the patient is intubated.  During extubation, care should be taken to remove the endotracheal tube while leaving the nasal feeding tube in place.
• Feeding tube placement is generally safe in patients with varices.  Although there is an increased risk of bleeding, feeding tube placement will often be necessary to adequately manage intubated patients with hepatic encephalopathy.  Please note that critically ill patients with cirrhosis may develop gastrointestinal bleeding spontaneously, so it's incorrect to attribute all bleeding to feeding tube insertion.

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treatments of desperation

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Fundamentally, there are two causes of hepatic encephalopathy:

1. Hepatic dysfunction (blood flowing through the liver isn't fully detoxified)
2. Shunting of blood around the liver

One approach to treatment of hepatic encephalopathy is to close any anatomic shunts which are allowing blood to bypass the liver.  This may be done in the following ways:

#1:  ligation of TIPS (trans-hepatic intra-portal shunt) 

• TIPS shunting may precipitate or worsen hepatic encephalopathy.
• In a patient with a TIPS shunt who has refractory hepatic encephalopathy, encephalopathy may be treated by closing the shunt entirely or revising it (to reduce its size).
• This is rarely done, because it would potentially aggravate other problems (e.g., the indication for the TIPS in the first place).

#2:  ligation of anatomic shunts

• Spontaneous shunts may develop which allow portal blood to flow into systemic circulation, bypassing the liver.  Some series suggests that spontaneous shunts are present in the majority of patients with refractory hepatic encephalopathy.(29705917)
  • Shunt may be suggested by refractory hepatic encephalopathy which seems disproportionate to the degree of derangement in liver function tests and coagulation.
• Spontaneous shunts may be found on CT scanning and ligated via interventional radiology.  Unfortunately, shunt closure may increase portal pressures – which may promote the formation of ascites and/or variceal bleeding.

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podcast

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Hepatic encephalopathy is a diagnosis of exclusion, so make sure to evaluate broadly for other problems.
• For patients with coma or stupor, don't delay treatment with rifaximin – start dual therapy with rifaxamin plus  lactulose or polyethylene glycol immediately.
• Make sure to treat any coexisting electrolyte disorders (especially lactulose-induced hypernatremia).  If lactulose is causing hypernatremia that is difficult to correct, consider transition to an isotonic solution of polyethylene glycol (e.g., GoLytely).
• Avoid long-acting neuroactive medications if possible (even benign-seeming medications like PRN opioids).

Guide to emoji hyperlinks 

•  = Link to online calculator.
•  = Link to Medscape monograph about a drug.
•  = Link to IBCC section about a drug.
•  = Link to IBCC section covering that topic.
•  = Link to FOAMed site with related information.
• 🎥 = Link to supplemental media.

One-minute recap:

PulmCrit Minute: Six pearls on hepatic encephalopathy
(fresh @iBookCC chapter here: https://t.co/no5LwvH0pT) pic.twitter.com/uQA1CJK1Le

— (@PulmCrit) May 30, 2019

Going further: 

• Hepatic encephalopathy:  Common precipitants, sneaky precipitants, and clinical pearls (Setareh Mohammadie and Amy Zeidan, emDocs)
• Hepatic Encephalopathy in the ED (Daniella Ohnemus, NU EM blog)
• 5 pearls on hepatic encephalopathy:  John Hwang, Marty Fried, and Shreya Trivedi, Core IM podcast