CONTENTS
- Rapid Reference 🚀
- Introduction
- Clinical features
- Diagnostic approach
- Treatment – overall strategy
- Podcast
- Questions & discussion
- Pitfalls
evaluation 📖
- Immediate fingerstick glucose.
- Review history & medication list.
- Basic labs (liver function tests, electrolytes including Ca/Mg/Phos).
- CT head if intracranial hemorrhage possible.
- Infection evaluation:
- Paracentesis if ascites is present (to exclude SBP).
- Chest X-ray.
- Urinalysis +/- urine cultures.
- Low threshold to obtain blood cultures.
- Consider lumbar puncture.
core therapeutic package
- 📦 Cathartic:
- 📦 Rifaximin 550 mg BID (initiate immediately).
- 📦 Thiamine 500 mg IV q8hr (impossible to exclude Wernicke encephalopathy 📖).
- 📦 Avoid sedating medications: 📖
- These patients are extremely sensitive to sedation (which may prolong or precipitate intubation).
- Intubated patients: use propofol or dexmedetomidine, avoid longer acting medications.
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. (36625084)
this chapter is about Type C hepatic encephalopathy
- 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.)
The diagnosis of hepatic encephalopathy often involves some combination of:
- Recognizing features of hepatic encephalopathy.
- Recognizing triggers of hepatic encephalopathy.
This may vary between different patients. In some cases, the trigger is obvious (e.g., a patient is admitted for gastrointestinal hemorrhage and subsequently becomes increasingly somnolent). In other cases, a careful evaluation is required to find the trigger (e.g., an occult infection manifesting with hepatic encephalopathy).
#1) manifestations of hepatic encephalopathy
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).
- Stupor/coma delaying extubation is a common manifestation of hepatic encephalopathy in the ICU.
clues to hepatic encephalopathy as the etiology of delirium
- Motor tone abnormalities:
- Asterixis. 📖
- Hyperreflexia, hypertonia, and clonus may also occur.
- Respiratory alkalosis often occurs in patients with cirrhosis, 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.
#2) triggers of hepatic encephalopathy
most common causes:
- #1 = Infection, especially:
- Spontaneous bacterial peritonitis. 📖
- Urinary tract infection.
- Pneumonia.
- GI bleed.
- Nonadherence with lactulose or rifaximin (or constipation).
- Dietary indiscretion with excessive protein intake.
- Volume depletion (e.g., over-diuresis).
- Electrolyte abnormalities (especially ⬇️ Na or ⬇️ K).
- Renal failure (including hepatorenal syndrome).
- Deliriogenic medications (especially opioids or sedatives).
less common causes:
- Transhepatic intravascular portosystemic shunt (TIPS), or spontaneous portosystemic shunts.
- Hepatic or portal vein thrombosis.
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.
- 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 (more on this below).
- ⚠️ 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).
A complete differential diagnosis of delirium is here: 📖 Below are more common considerations in a patient with cirrhosis.
medications & toxicologic
- Patients with cirrhosis are often very sensitive to medication-induced delirium.
- Alcohol intoxication.
- Alcohol withdrawal vs. hepatic encephalopathy discussed here: 📖
infection
- Spontaneous bacterial peritonitis.
- Pneumonia.
- Urinary tract infection.
- CNS infection (meningitis, encephalitis).
metabolic
- Wernicke encephalopathy
- Hypoglycemia.
- Uremia (e.g., hepatorenal syndrome).
- Electrolyte abnormality (especially sodium).
neurological primary process, e.g.:
- Subdural hematoma (may present without localizing findings).
- Seizures (especially SESA syndrome 📖).
liver function tests
- These will usually be abnormal (reflecting underlying cirrhosis).
- Hepatic encephalopathy can occur with normal liver tests (liver tests aren't tremendously sensitive for cirrhosis).
ammonia
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.
approach to optimize the value of ammonia measurement:
- Ideally obtain an ammonia level in a fasted patient.(36625084)
- Avoid venous stasis (tourniquet, fist clenching).
- Collect the sample on ice and send to the lab STAT.
- (Note that either a venous or arterial specimen is fine).
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.
- (Seizures can occur in the context of hepatic encephalopathy, but this isn't a common finding. It should raise concern for an alternative underlying CNS process.)
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).
role of neuroimaging
- 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 is obtained less often, but may be useful to exclude alternative pathologies (especially among patients who are not responding to therapy for hepatic encephalopathy).
(1) findings associated with chronic hepatic failure
- Bilateral, symmetric T1 hyperintensity in the globus pallidi and substantiae nigrae (or less commonly involving the pituitary gland and hypothalamus).(31589567)
- This is commonly seen among patients with chronic hepatic failure. Manganese accumulation in the brain seems to be the cause, as a result of portosystemic shunting that bypasses liver uptake of manganese.
(2) findings associated with acute hepatic encephalopathy
- Although cerebral edema is more typically associated with acute liver failure, this may even occur in chronic hepatic encephalopathy.(31589567)
- Diffuse cortical/subcortical edema may occur that causes T2/FLAIR hyperintensity and restricted diffusion.(Tang 2015)
- Symmetric involvement of the insula (most commonly), cingulate gyrus, and thalamus may be especially suggestive.
- There tends to be relative sparing of the perirolandic and occipital regions.
- Vasogenic edema may also involve the cerebral white matter (especially the corticospinal tract and posterior limb of the internal capsule).
- 💡 Hepatic encephalopathy is a common cause of acute toxic leukoencephalopathy.
- (SWI/GRE sequences may show microhemorrhages in about half of patients, but this doesn't appear to affect clinical outcomes.)
- More on imaging in hepatic encephalopathy: 🌊
The overall picture of patients with severe hepatic encephalopathy is a little complicated.
long-term prognosis is guarded
- The overall prognosis is generally poor, unless patients are candidates for liver transplantation. For example, hepatic encephalopathy may be associated with a one-year survival of ~40% and a three-year survival of 20%.(33838857, 36625084)
- Discussions regarding prognosis and goals of care should be pursued with the patient's family.
short-term prognosis is often reasonably favorable
- An organized and aggressive strategy is usually successful in waking up the patient sufficiently to liberate from mechanical ventilation.
- Success involves simultaneous implementation of numerous interventions, as outlined in the sections below.
- Don't implement one intervention and wait for it to fail; instead, begin maximally aggressive therapy up-front and wean off treatments as the patient improves.
Either lactulose or polyethylene glycol are required. For patients whose primary problem is hepatic encephalopathy, polyethylene glycol is preferred. Alternatively, for patients with mild hepatic encephalopathy, lactulose may be sufficient.
🏆 polyethylene glycol
basics
- Polyethylene glycol (PEG) is an inert osmotic cathartic agent.
- Polyethylene glycol is widely used to prepare the colon prior to colonoscopy.
evidentiary basis
- Safety: Polyethylene glycol has been widely utilized prior to colonoscopy for years, in a variety of different patient populations. It is generally accepted to be safe.
- Efficacy: 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)
advantages of polyethylene glycol
- (1) When diluted in large volumes of water, polyethylene glycol has little effect on electrolyte levels of volume status.(11246353) In contrast, aggressive lactulose therapy removes water from the body – which may lead to hypernatremia and volume depletion.
- (2) Complete removal of stool from the bowel is expected to be a highly effective strategy for minimizing fecal ammonia production.
- (3) Utilization of a colonoscopy preparation protocol may be more uniformly effective than lactulose (lactulose has a tendency to be under-dosed initially).
dosing of polyethylene glycol
- These studies used a pre-colonoscopy regimen of polyethylene glycol (e.g., ~4 liters over ~ 4 hours).
- Note that a commercial preparation of polyethylene glycol should ideally be utilized (including reconstitution with large volumes of water), in order to avoid electrolyte shifts.
lactulose
basics
- Lactulose works via numerous potential mechanisms (e.g., lowers the colonic pH which traps ammonia in the gut, laxative agent, promotion of non-ammonia-producing bacteria such as lactobacillus). It is supported by a 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).
situations where lactulose is especially useful
- Polyethylene glycol is arguably a front-line agent for many patients. However, there are some situations where lactulose is especially useful:
- (1) Patients with a combination of hepatic encephalopathy plus hyponatremia. Lactulose will treat both of these problems (lactulose pulls water osmotically out of the body, thereby increasing the sodium concentration).
- (2) Mild hepatic encephalopathy (which doesn't merit polyethylene glycol).
- Rifaximin is a non-absorbable 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 dose is 550 mg PO BID.
Common triggers of hepatic encephalopathy are listed above. 📖 These should be evaluated and managed. Some frequent management issues include the following:
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 is an osmotic cathartic agent, so it removes water from the body and increases the sodium concentration. Lactulose alone is generally a very effective treatment for both hyponatremia and also hepatic encephalopathy.🌊
- 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.📖
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.)
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.
Fundamentally, there are two causes of hepatic encephalopathy:
- Hepatic dysfunction (blood flowing through the liver isn't fully detoxified)
- 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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- 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 rifaximin plus lactulose or polyethylene glycol immediately.
- Avoid long-acting neuroactive medications if possible, as patients with hepatic encephalopathy are usually very susceptible to over-sedation.
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References
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