Brain and the Liver: Cerebral Edema, Hepatic Encephalopathy and Beyond
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Occurrence of brain dysfunction is common in both chronic liver disease as well as acute liver failure. While brain dysfunction most commonly manifests as hepatic encephalopathy is chronic liver disease; devastating complications of cerebral edema and brain herniation syndromes may occur with acute liver failure. Ammonia seems to play a central role in the pathogenesis of brain dysfunction in both chronic liver disease and acute liver failure. In this chapter we outline the pathophysiology and clinical management of brain dysfunction in the critically ill patients with liver disease.
KeywordsHepatic encephalopathy Acute liver failure Fulminant hepatic failure Chronic liver failure Acute-on-chronic liver failure Hepatic coma Intracranial hypertension
Review the classifications, mechanisms and neuroimaging findings involved in hepatic encephalopathy
Differentiate the risk factors and implications of hepatic encephalopathy in acute Liver failure and Chronic Liver Failure
Recognize and distinguish the approach to evaluating and managing hepatic encephalopathy and its confounders in critically ill patients with acute and chronic liver failure
Outline the organ system approach to ICU considerations in hepatic encephalopathy applicable to acute and chronic liver failure
Hepatic encephalopathy (HE) represents brain dysfunction directly caused by liver insufficiency and or portosystemic shunting (PSS) that manifests as a wide spectrum of neurological and psychiatric deficits ranging from subclinical deficits to coma.
8.2 Classification of HE
Classification and grading of hepatic encephalopathya
Classification of HE
Sub classification of HE
Defining feature and description
1. Underlying diseasea
Acute Liver Failure
Portal-systemic Bypass without intrinsic hepato-cellular damage
Cirrhosis and portal hypertension with portal-systemic shunts
2. Severity of Manifestationb
Psychometric or neuropsychological alterations without clinical evidence of mental change
Trivial lack of awareness
Euphoria or anxiety
Shortened attention span
Impairment of addition or subtraction Altered sleep rhythm
Lethargy or apathy
Disorientation for time
Obvious personality change Inappropriate behavior
Somnolence to semi stupor Responsive to stimuli
3. Time course of presentation
Single or episodes occurring >6 months
Episodes occur <6 months
Behavioral alterations that are always present and interspersed with relapses of overt HE.
4. Precipitating factors
Precipitating factors can be identified in nearly all bouts of episodic HE type C and should be actively sought and treated when found
8.3 HE, Cerebral Edema and Mortality in ALF and Overt Type C HE
Cerebral edema (CE) at the cellular level (cytotoxic edema) or interstitial level (vasogenic edema) is a pathophysiologic hallmark of HE in both acute and chronic liver failure. In chronic liver failure, the occurrence of CE is not apparent on a macroscopic level. Hence the edema is not visible on conventional brain imaging, causing the clinician no concerns for elevated intracranial pressure (ICP). In acute liver failure, intracranial hypertension (IH) is a looming concern to the clinician. The term intracranial hypertension (IH) specific to ALF, implies both a cause and effect. The cause refers to diffuse CE visible on brain imaging and the effect refers to elevated ICP and impending transtentorial herniation if left untreated.
Acute liver failure (ALF) is a devastating disease with mortality up to 40–50% due to progressive multiorgan failure . Worsening HE in ALF heralds a grim a prognosis. Grade IV HE precedes the development of cerebral edema and IH culminating in transtentorial herniation. Historically the progression from HE to transtentorial herniation accounted for up to 75–80% of deaths in ALF [4, 5]. With improved ICU care focusing on neuroprotective interventions, the mortality attributable to IH is in the range of 10–20% .
Despite the absence of IH, the diagnosis of HE in chronic liver failure is associated with a 50% mortality at 1 year. The correlation between Type C HE and increased mortality in cirrhosis has been difficult to decipher due the heterogeneity of the occurrence and impact of accruing multi-organ failure. Acute-on-chronic liver failure (ACLF) remains a term in search of a more precise definition that accurately captures a dominant subset of decompensated cirrhotics with disproportionately high short-term mortality rates attributable to multiorgan failure. In the recent European Canonic study, ACLF was distinctly defined by the sequence and severity of organ dysfunction, allowing for a better understanding of the implications of HE in this critically ill subgroup [7, 8]. HE in both decompensated cirrhosis and ACLF was independently associated with increased mortality. However, mortality from HE associated with ACLF was significantly worse than the HE associated decompensated cirrhosis  and therefore warrants closer monitoring and early transfer to the ICU.
Unlike ALF, IH does not occur in decompensated cirrhosis but is infrequently reported in ACLF [10, 11]. The rare occurrence IH in ACLF is predicated upon the acuity of the liver injury rather than the chronicity of the liver disease . A more recent retrospective study noted that cerebral edema leading to tonsillar herniation and death was observed in 4% (3/48) of patients with ACLF .
Malignant cerebral edema resulting in intracranial hypertension and brain herniation appears to rely on secondary mechanisms specific to ALF. While cytotoxic edema is an explicit feature in HE, its immediate contribution to malignant edema or intracranial hypertension is dubious. In cirrhotics with HE, cytotoxic edema is present on a cellular level but often unappreciable on CT imaging. Vasogenic edema it thought to lag temporally behind cytotoxic edema and is both direct and indirectly attributable to ammonia [27, 28, 29]. Luxury perfusion due to increased cerebral blood flow and impaired autoregulation appears to be a process specific to ALF that accounts for the development of malignant cerebral edema and intracranial hypertension. Mechanisms driving this process include the loss of integrity of blood brain barrier , failure of ATPase pump with resultant hyperemia due to loss of cerebrovascular autoregulation, increased NO production due to increased activity of neuronal nitric oxide synthase , up regulation of cyclooxygenase with increased production of prostaglandins and eicosanoids resulting in hyperemia and increased cerebral blood flow . Hyponatremia frequently occurs in ALF and likely contributes to increased interstitial water and the cerebral edema. Targeting higher plasma sodium goal is associated with a lower incidence of intracranial hypertension.
In chronic liver failure, the brain has time to adapt to the deleterious effects of chronic ammonia exposure . Cerebral astrocytes have the capacity to convert ammonia into glutamine. In chronic liver failure, intracellular glutamine accumulation is offset by the export of organic osmoles (myo-inositol and taurine) from astrocytes to maintain osmotic balance and mitigate the development of cytotoxic edema.
Glutamine in turn prevents reuptake of glutamate which accumulates in post synaptic space. In chronic liver failure, there is compensatory decrease in glutamate receptors in post synaptic membrane which may account for the psychomotor slowing and drowsiness seen in HE. Other mechanisms of HE includes the elevated GABAergic tone produced by stimulation of TGR5 receptors and increased neurosteroid production by activation of peripheral type benzodiazepine receptors.
The failing liver triggers a systemic inflammatory response with activation of immune system and release of cytokines including IL-6, IF-α, TNF-α. The mechanism of increased cytokines involves activation of toll like receptors which activate Kupffer cells that activate signaling cascades and transcription of proinflammatory cytokines. These cytokines increase cerebral blood flow and increase permeability for ammonia. While this process contributes to HE in chronic liver failure, it transpires on a mammoth scale in ALF.
8.5 Clinical Features of Hepatic Encephalopathy in Chronic Liver Disease
In the undifferentiated liver failure patients with abnormal synthetic liver function, the absolute first critical step is to distinguish if the HE is type A (ALF) or type C (Chronic). This step helps stratify risk attributable to the HE and designates appropriate neuromonitoring and neuroprotective interventions. While this may seem intuitive, confusing these disease entities is not uncommon in clinical practice and results in unnecessary delays that affect patient outcome. In autoimmune hepatitis, differentiating the two can at times be difficult due to derangements in synthetic function common to both in early stages. A careful history, and longitudinal monitoring of neurological status and synthetic function will be needed to make this determination. In the indeterminate phase, it is prudent to adopt an ALF management strategy until the clinician can safely determine the acuity and chronicity of the disease.
If the initial presentation of HE in chronic liver failure is atypical or severe (grade 3 or 4 HE), excluding an alternate etiology due to infection, metabolic anomaly, toxidrome, neurovascular event or seizures through an accurate history, physical exam, laboratory work up and brain imaging is paramount. If the mental status decline of HE (grade 1 to grade 4) is witnessed with typical features and a precipitant identified, extensive work up for an alternate etiology is less warranted.
8.6 Neurological Assessment in Early HE
Evaluating orientation and serial subtraction test to assess attention are one of the more objective determinations of earlier stages of HE specifically WH grade I to II. Other neuropsychiatric findings are more subjective and can be difficult to quantify and trend. The more contemporary Confusion Assessment Method (CAM ICU) and Agitation Sedation Scale (RASS) used in ICUs may provide some additional benefits to discriminating the neuropsychiatric changes and the level of arousal respectively, however, neither have been adequately validated in HE .
Grading asterixis to monitor progression of hepatic encephalopathy 
Grade of asterixis
Number of flaps/30 s
No flapping motions
Rare flapping motion
Occasional, irregular flaps
Comparable Glasgow Coma Scale to Modified West Haven Criteria adapted from Bernal et al. 
West Haven Criteria Grade
8.7 Physical Exam in HE
A complete neurological examination in severe HE is likely to uncover false localizing signs including transient pupillary dysfunction, dysconjugate gaze, gaze deviation, ocular bobbing, decorticate and decerebrate posturing, hyperreflexia, up going plantar as well as other less common findings. These findings are usually transient and resolve or change within hours. Cases of reversible focal deficits mimicking stroke attributable to severe HE has been reported but fortunately these are not common.
8.8 Brain Imaging in Overt Type C HE
In patient with low grade HE (WH grade I or II) developing sudden focal deficits i.e. face, arm and leg weakness that is clinically localizable, a CT if negative for hemorrhage should be followed up by an immediate CT-Angiogram before considering thombolytics. MRI would also be helpful in this situation if it can be performed quickly. Initiating thombolytics with a negative CT alone would not suffice due to the coagulopathy and higher bleeding risk in cirrhotics and the potential that the source of the deficit was predominantly a metabolic abnormality and not a vascular phenomenon.
In a single center study of 158 cirrhotic patients scanned for altered mental status, Joshi et al. revealed that 30% of head CTs were normal, 30% demonstrated increased atrophy, 17% with small vessel disease and 16% with intracranial hemorrhage . The prevalence of intracranial hemorrhage (ICH) in ACLF was higher than decompensated cirrhosis: noted to be 23% versus 9% . Given this finding, the decision to image a patient HE requires clinical discretion. If a patient with recurrent HE, presents with his/her usual presentation for HE that was witnessed by family or hospital staff, then imaging would less likely be of use. If an unresponsive patient was found on the ground, demonstrates evidence of trauma from a fall, witnessed fall or atypical presentation of HE, imaging with CT should be performed. Findings by Joshi et al. also implies that a lower threshold for performing CT should be considered in patients with ACLF possibly due to the more coagulopathic state evidence by lower platelet counts, higher INRs and lower fibrinogen levels.
While the risk of IH leading to herniation is low in cirrhosis, the infrequent occurrence IH in ACLF (4%) is predicated upon the acuity of the liver injury rather than the chronicity of the liver disease [12, 13]. Therefore, infrequently, an obtunded ACLF patient with abrupt deterioration in synthetic liver function, who is relatively young, with significant hyperammonemia, hemodynamic instability, multiorgan failure, hyponatremia, very recent TIPSS procedure or volume overload should be considered for imaging to evaluate for cerebral edema and herniation.
MRI may be useful in evaluating atypical features or refractory HE for alternate causes, both common and rare. More recently, an underrecognized complication of prolonged course of metronidazole used for management of HE in cirrhotics with impaired renal function has been identified with explicit MRI finding [37, 38, 39]. MRI may also detect cerebral edema more precisely than CT however, the infrequent ACLF patients suspected of having cerebral edema is likely too critically ill to tolerate an MRI.
8.9 Precipitating Factors for Overt Type C HE
Precipitating factors, HE-confounders and underlying mechanisms in hepatic encephalopathy
Precipitating Factor and HE-confounders
Work up to consider
Excess nitrogen burden
Excess dietary protein
Protein catabolism in starvation and insulin resistance due to Diabetes Mellitusa
Portosystemic shunta (iatrogenic and spontaneous)
Complete blood count
BUN and Creatinine
Micronutrients—B12, B6, Thiamine, Carnitine level
Plasma ammonia levels
Blood Glucose and HBa1c
Abdominal venous imaging
Infection and inflammation
Viral or Autoimmune Encephalitis
Blood, Urine, CSF, Sputum culture, C. difficile toxin
Ascitic fluid cell count and culture
ScvO2 and Lactate
Serum and CSF Cryptococcus antigen
Lipase and amylase
Compromised toxin clearance
Dehydration due excessive fluid restriction, diuretic usea or paracentesisa, diarrhea
Acute Kidney Injury, Hepatorenal Syndrome
Hypotension due to bleedinga, or systemic vasodilatation
Abdominal Compartment syndrome due to severe ascites
Electrolytes (serum Sodium)
ScvO2 and Lactate
Monitor Bladder Pressures
Compromised neurotransmission and metabolism
Endozepines and neurosteroids
Coinciding Alcohol withdrawal
Hypoxemia and Hypercarbia
Blood alcohol level
Acute hepatocellular damage
Other acute hepatitis
Development of hepatocellular carcinoma
Undiagnosed Wilsons Disease
Liver function panel
Acute Hepatitis work up
Alpha fetoprotein level
Serum and 24-h urinary Copper, Ceruloplasmin,
Other confounders: metabolic abnormalities, neurological injury
Intracranial Hemorrhage (Subdural Hemorrhage is most common cause)
Metronidazole induced encephalopathy
Central Pontine Myelinolysis
Brain Stem Strokes
MRI brain with and without gadolinium
List of clinical features and precipitating factors for HE in decompensated cirrhosis versus ACLF—canonic studya
HE in decompensated cirrhosis
HE in ACLF
• Older Cirrhotics
• Inactive Drinkers
• Less impairment of Liver function
• Minimal inflammatory reaction
• Low prevelance of organ failure
• Lower mortality
• Young Cirrhotics
• More frequently Alcoholics
• More Impairment in Liver function
• Increased inflammatory response
• High prevalence of organ failure
• Higher mortality
• Long term diuretic use
• Active alcohol use
• Bacterial infections
55 year old male with Hepatitis C related Cirrhosis is having recurrent HE occurring frequently and causing recurrent admissions. In addition to his liver disease, he has stage III Chronic Kidney Disease for which is being evaluated for a combined Liver and Kidney Transplant. He is being treated with a HE regime of daily doses of Lactulose, Rifaximin, Zinc and Metronidazole for the last 12 weeks for the refractory HE. He has become increasingly altered in the past week and presents to the Emergency department with seizures that subsided with Ativan 2 mg and was subsequently intubated.
Heart rate: 90 bpm Respiratory Rate: 12 bpm BP: 112/70 Temperature: 36.8 °C
Neuro: Pupils 3 mm reactive to light. Brisk reflexes throughout with upgoing plantar reflexes. Remains minimally responsive with GCS 7. Moving all four extremities with equal strength.
CVS: Normal heart sounds. Sinus rhythm. No murmurs
Pulmonary: Clear to auscultation bilaterally
GI: Ascitic abdomen and nontender to palpation.
Extremities: Normal pulses. Trace edema.
Laboratory and Diagnostics:
His plasma ammonia level is 89 mmol/L. He is afebrile. Ascetic fluid cell count is normal. Urine analysis with 12 wbc and the urine has been sent for culture. His chemistry panel and liver function panel remains unchanged from his last outpatient visit. EEG revealed periodic lateralizing discharged from both parietal lobes suggesting cortical irritability for which Levetiracetam IV has been initiated.
What diagnostic test would you order?
How would you treat his encephalopathy?
Discontinue Metronidazole. Continue Lactulose and Rifaximin.
This is a case of Metronidazole Induced Encephalopathy (MIE). The patient is at risk due to decreased clearance with both liver and kidney dysfunction. Metronidazole is not infrequently used off label to treat refractory HE. When used indiscriminately, accumulation of Metronidazole causes neurotoxicity affecting both peripheral nerve and central white mater. This patient had bilateral symmetrical parietal white mater demyelination and edema seen on MRI which is consistent with MIE. With supportive care, management of seizure and discontinuing metronidazole, most patient will improve with time. Limit Metronidazole use in cirrhosis to 7 days or less when possible.
8.10 Goals of Therapy for HE in Chronic Liver Failure
- 1.Identifying if HE is presenting with decompensated cirrhosis versus ACLF.
ACLF patient will require earlier transfer to the ICU due to imminent short-term mortality
Treatment of precipitating factors in parallel with intensive care supportive strategies for multiorgan failure
- 3.Initiation of first tier therapeutic strategies specific to HE
Reduction of intestinal ammonia production and absorption
Nutritional and micronutrient supplementation
- 4.Initiation of second tier therapeutic strategies specific to HE
Plasma ammonia lowering devices and non-pharmacological interventions
Eliminating large spontaneous portosystemic shunts (SPSS)
Alternative pathway therapies
Distinction of ACLF has been discussed previously and the importance of this will not be repeated here. Vast majority of patients with HE have a precipitating cause: some of the commoner precipitating causes are upper GI bleeding, infections including spontaneous bacterial peritonitis, hypovolemia and over-diuresis, hypokalemia, metabolic alkalosis, concomitant use or abuse of other sedating drugs, particularly benzodiazepines. Precipitating cause should be actively sought and treated in parallel with best supportive care. Most patients with cirrhosis have protein energy malnutrition and as such there is no role of protein restriction in management of acute or chronic HE. Hypokalemia should be corrected. Hyponatremia should be avoided particularly in ALF and ACLF: however rapid correction of Na avoided due to risk of osmotic demyelination syndrome.
8.11 Therapeutic Strategies for Managing Type C HE in the ICU
8.11.1 Plasma Ammonia Lowering Strategies (First Tier)
- 1.Reduction of intestinal ammonia production and absorption
Lactulose (beta-galactosidofructose) and Lactitol (beta-galactosidosorbitol)
Despite the absence of mortality benefit, both these nonabsorbable disaccharides are currently first line agents for the treatment of HE. Lactitol is not available in the United States. Since there is absence of specific disaccharidases on the villous membranes of the human small bowel, these disaccharides freely reach the colon. In the colon, they are broken by the colonic bacteria into acids which lowers the pH. This acidification favors conversion of ammonia (NH3) into ionic ammonium (NH4+). Because of its very nature, ammonium ion is less permeable than ammonia and less absorbed into portal circulation. In addition, both lactulose and lactitol inhibit ammoniagenic coliform bacteria and clear ammonia by decreasing transit time. Lactulose is superior to placebo and tap water enemas and comparable to neomycin [41, 42]
Lactulose is usually given orally in patients who are awake enough to swallow. Initial dose of 30–60 ml can be repeated hourly till there is a bowel movement and then dose titrated to 2–3 soft bowel movements per day. Caution should be exercised in patients with significant alteration in mental status and high aspiration risk. In addition, it should be recognized that goal of lactulose administration is not profuse diarrhea: resulting hypovolemia may actually make encephalopathy worse. Finally, lactulose can cause significant gaseous small bowel distension in paralytic ileus and make it worse. A distended abdomen in a critically ill cirrhotic patient receiving lactulose should be evaluated for an ileus and not assumed to be increased ascites. Lactulose can also be given as enema in comatose patients and those unable to swallow or lacking enteral access.
Polyethyelene Glycol (PEG)
A small randomized single center study demonstrated that a 4 L PEG administered orally or via NG over 4 h led to more rapid HE resolution despite less ammonia difference at 24 h compared to standard therapy with Lactulose. PEG’s safety profile and balanced electrolytes make it an attractive adjunct to Lactulose in the ICU setting. Volume of 4 L remains a concern for aspiration especially in later grades of HE.
Ammonia lowering antibiotics (First Tier)
Rifaximin: Rifaximin is an oral nonsystemic antibiotic with <0.4% absorption. Rifaximin has in vitro antimicrobial activity against Gram-positive and Gram-negative, aerobic and anaerobic flora. Current AASLD/EASL guidelines only recommend rifaximin as an add-on therapy for prevention of overt HE recurrence. Data is insufficient regarding the use of rifaximin as a first line therapy or stand-alone therapy for treatment of overt HE. Rifaximin may be used in combination with lactulose in patients with overt HE as the combined effect leads to reversal of the condition in 76% of patients vs. 50.4% in those on lactulose alone. In absence of more robust data, rifaximin 550 mg po q12h is a reasonable adjunct for severe or refractory HE, especially since it has a better side effect profile than neomycin and metronidazole. Rifaximin added to lactulose is more efficacious than lactulose alone in prevention of overt HE (43)
Neomycin: Oral neomycin is minimally absorbed, yet chronic administration can result in nephrotoxicity and ototoxicity. Evidence for use and efficacy of neomycin in HE is not robust at all, yet it is FDA approved [43, 44]. For acute HE, 1 g q6h for up to 6 days and for chronic HE, 1–2 g daily is prescribed. Given other alternatives and lack of strong evidence, use of neomycin should probably be limited
Metronidazole: Not FDA approved for management of HE. One small study revealed at it is as effective at Neomycin at a dose of 250 mg twice daily . The concern for resistant clostridium difficile colitis and neurotoxic effects of metronidazole are valid. Liver failure and renal impairment are both predisposing factors to developing metronidazole encephalopathy (MIE), a toxidrome more recently characterized by both reversible and irreversible findings on MRI [37, 38, 39].
Nutritional and micronutrient supplementation (First Tier)
Zinc: There are a number of small studies on Zinc supplementation in cirrhosis resulting in lower plasma ammonia levels and improved hepatic encephalopathy. The biochemical rational is predicated on Zinc being a co-factor in the urea cycle. Two recent meta-analysis on zinc in HE revealed a significant neuropsychiatric improvement measured using the number correction test . In the meta-analysis by Timbol et al. published in abstract form., zinc supplementation provided for a statistical significant reduction in serum ammonia levels . Zinc levels are tightly associated with liver function. Cirrhotics with low zinc levels have a higher risk of hepatic decompensation and hepatic encephalopathy. In cirrhosis with hypoalbuminemia, low zinc levels may be reported since 80% of zinc in blood is albumin bound. Zinc levels are not routinely monitored unless a way to measure free plasma zinc level is developed. In the critically ill patient with HE, including zinc supplementation has the potential to improve ammonia metabolism with minimal side effects. However, long term use of zinc supplementation in concomitant renal failure does increase the possibility of zinc toxicity.
l-Carnitine: There are numerous small studies and anecdotal reports about the ammonia lowering effects of oral supplementation with l-Carnitine which requires further study. Carnitine is a co-factor in the metabolism of long chain fatty acids. It facilitates mitochondrial membrane transport by binding acyl-CoA molecules and promotes translocation from cytoplasm to mithochondrial matrix for B-Oxidation. Disruption in Carnitine transport results in cytosolic accumulation of fatty acyl-CoA molecules which is postulated to inhibit the urea cycle . Patient with carnitine deficiency due to malnutrition or short gut, valproate acid, primary deficiency due to mutations in organic cation transporter gene (OCTN2) have been reported to manifest with symptomatic hyperammonemia which improves with carnitine supplementation. There is limited evidence on use l-Carnitine routinely in the management of HE, however, in cirrhotic patients with a significant history of malnutrition and refractory hyperammonemia, checking l-Carnitine levels followed by supplementing l-Carnitine pending the return of these levels is physiologically sound and may provide a benefit with minimal risk until further evidence is available.
Branched-chain amino acid (BCAA) supplementation: Improvement in HE has been noted in patients predominantly treated in the outpatient setting without improvement in mortality. Existing evidence revealed no difference between BCAA, lactulose and neomycin It did however increase the risk of nausea and vomiting. Its role in the ICU remains unproven. Having an alternative to lactulose in patients on vasopressors or at risk of developing an ileus could be useful in the critical care setting.
- 4.Plasma Ammonia lowering devices and non-pharmacological interventions (second Tier)
Continuous Renal Replacement Therapy
Continuous renal replacement therapy using continuous veno-venous hemofiltration with high filtration volume (90 ml/kg/h) is an effective method of rapidly lowering serum plasma ammonia levels [49, 50]. Ammonia clearance is closely associated with ultrafiltration rate. More than likely, CRRT will be used in such a patient for acute kidney injury needing renal replacement; and not hyperammonemia per se. However, one can make a case for CRRT for severe hyperammonemia particularly in ALF or ACLF where the risk of intracranial hypertension and herniation is significantly higher. Hemodialysis and CRRT remains the mainstay for the management of hyperammonemia in patients with urea cycle disorders with a proven track record.
Molecular Adsorbent Recirculating System (MARS) and Bio-artifical devices
Molecular Adsorbent Recirculating System (MARS) is a blood detoxification system based on albumin dialysis that removes protein bound (bile acids, bilirubin, endogenous benzodiazepines, nitrous oxide) and water soluble toxins (ammonia, creatinine). In the US, MARS is FDA approved for management of ALF due to drug overdose or toxic exposures and for management of HE in decompensated cirrhosis. MARS trials thus far have failed to show a survival benefit; however they have consistently demonstrated improvement in HE and a satisfactory safety profile. Using MARS for refractory HE is thus a potential option. In the case of bioartificial systems, the extracorporeal circuit includes bioreactors loaded with liver cells, thus theoretically having potential to improve synthetic function as well. These extra-corporeal liver assist devices are as of now far from ideal and not widely available; these are subject of research.
Therapeutic Hypothermia (Goal Temperature of 34 °C)
There remains limited clinical experience in the use of mild hypothermia in chronic liver failure . Its appeal in liver disease is that it counteracts many of the metabolic effects of ammonia, slows protein catabolism and production of ammonia by bacteria and the kidneys . The predominant concern with using hypothermia in cirrhotic patients is its potential to worsen the existing coagulopathy in patients who are high risk for bleeding and the predisposition to infection. In rare cases of extreme refractory hyperammonemia, hypothermia can be used as a transient neuroprotective strategy while pursuing clearance of plasma ammonia through other avenues.
- 5.Alternative pathway therapy (second Tier):
Ammonia scavengers: Sodium Benzoate, phenylacetate, glycerol phenylbutyrate, Ornithine phenylacetate
l -Ornithine l -Aspartate (LOLA)
Ammonia scavengers help to increase ammonia clearance and thus reduce systemic concentrations of ammonia. These compounds provide an alternative pathway wherein ammonia is excreted in the urine as phenylacetylglutamine. Whereas small randomized studies show encouraging results, larger trials are needed to define the role of these in HE in daily practice. Limitation of these therapies include the need for intact renal function for elimination of phenylacetylglutamine. Efficacy of therapy with dialysis remains unclear. Sodium benzoate is an FDA approved food additive/preservative and is infrequently off-lable in refractory hyperammonemia by adding it to enteral feeding in patients with refractory hyperammonemia and intact renal function. However, the efficacy of this therapy in cirrhosis have not been verified in large trials.
l-ornithine l-aspartate (LOLA) : LOLA is substrate for urea cycle and stimulates enzymatic activity in residual hepatocytes leading to increased urea excretion. LOLA significantly improves HE and ammonia levels when compared to placebo; however it demonstrated no difference compared with lactulose. Oral LOLA is more frequently used for treatment of HE outside the US.
Neurotransmitter Blockade (second Tier)
Flumazenil : In a systematic review involving 13 controlled trials with a total of 805 patients, the use of flumazenil was associated with significant improvement in HE but failed to show long term benefits or improvement in outcome . As a short acting benzodiazepine antagonist, flumazenil is postulated to inhibit endogenous GABAergic substances and previous residual effects of long acting benzodiazepine. Cirrhotics have also been shown to have increased benzodiazepine receptor activation but only a subset of patients will demonstrate response to Flumazenil. Flumazenil should be used in a closely monitored environment as it has a potential of provoking seizures. A trial of 1–2 mg of Flumazenil in 20 mL saline solution by intravenous infusion for 3–5 min may be considered in patients with stage 3–4 encephalopathy who have low serum ammonia level and have not responded to Lactulose.
Surgical Treatment Options if applicable (second Tier)
Embolization of large portosystemic shunts (PSS): A review by Lyn AM et al. of their carefully selected 20-patient experience with embolization of portosystemic shunt for refractory HE revealed that durable benefit in HE was achieved in majority of patients with reduction in hospitalization for HE . Increased ascites was noted in a about 50% of these patients. Multiple case reports and case series have corroborated these findings, however, larger supporting studies especially in the ICU setting remains deficient. PSS embolization could be considered in the refractory, recurrent or persistent HE in select patients. At present, this option is probably underutilized given that imaging for large portosystemic shunts are often not routinely performed for evaluation of refractory HE.
Liver transplantation: is the definitive treatment for HE . Tier 1 and 2 interventions should be thoughtfully and diligently employed to patients eligible for transplant as pre-transplant encephalopathy post-transplant metabolic encephalopathy. An awake, oriented and responsive candidate is also a more attractive candidate for transplantation.
8.12 Acute Liver Failure
8.12.1 Clinical and Laboratory Assessment Specific to Type A HE (ALF)
In type A HE due to ALF, grading scales for HE do not differ from type C HE (see Neurochecks in HE) which include clinical assessment WH grading, asterixis grading, GCS. However, the consequences of progressing to grade 4 HE is significantly worse in ALF due to the significantly higher risk of IH resulting in brain herniation. It is imperative that early determination of acuity of the liver failure need to be ascertained which should trigger a rapid transfer of the patient to a regional liver transplant program. ALF patients can rapidly decline clinically with distributive shock and multiorgan failure after which they are too unstable to a transfer.
8.12.2 Neuro Checks in ALF
Monitoring pupillary function is important in WH grade 3 and 4 HE. Pupillary light reaction frequently progresses from normal to hyper-responsive in early in WH grade 2-3 HE and hypo-responsive in WH grade 4 . Loss of pupillary function may be a metabolic phenomenon in late stages however it may also signify brain herniation due to uncal compression or stretching of ciliary fibers of cranial nerve III. Hence, despite the false positive findings, close monitoring of pupils is critical in ALF. Reversal of brain herniation using osmotherapy is possible if detected early.
Reports of up to one third of WH grade IV ALF patients may develop subclinical seizures. Presence of subclinical seizures are of uncertain relevance but could contribute to elevated ICP inpatients with IH. Continuous EEG should be considered during the management of Grade IV HE with risk factors for developing IH.
8.12.3 Objectives of Serial Laboratory Testing Relevant to HE and IH in ALF
Analyze and monitor the onset and severity ALF and examine for evidence spontaneous recovery of liver function. Risk of cerebral edema is analogous to severity of liver dysfunction and hyperammonemia but resolution of cerebral edema may lag behind the recovery of synthetic liver function.
- 2.Decelerating the development cerebral edema:
Monitor plasma sodium levels, osmolarity, pH, CO2, plasma ammonia levels
Correct hyponatremia, severe acidosis, hypercarbia
Augment plasma sodium levels and osmolarity
Monitoring other organ function, detection of infection and hemodynamic laboratory markers pertinent to cerebral perfusion and brain edema.
Triggering the decision to transplant based upon clinical picture in conjunction with biochemical markers before losing the hemodynamic window.
8.12.4 Risk Factor for Development of IH in ALF
Plasma ammonia level of more than 150–200 μmol/L is associated with the development of IH in ALF. More recently, Kitzberger at al. reported that 25% of ALF patients developed IH despite relatively low plasma ammonia levels (NH3 < 146 μmol/L) . The disproportionately higher extra-cerebral severity of organ failure (SOFA) score in these patients emphasizes the substantial role of inflammation and shock organ failure in the development cerebral hyperemia and diffuse cerebral edema. Other common associations for ICP elevation include hyponatremia, volume overload, severe hypercarbia, severe acidosis, pain and ventilator dyssynchrony.
8.12.5 Brain Imaging in ALF and IH
Utility of brain CT for assessment of cerebral edema and IH remains in question especially when interpretation of CT is performed without a comparator. Imaging is useful for excluding other intracranial processes or evaluating for complications of placing intracranial devices [58, 59]. If imaging is to be used for CE detection and to assess risk of herniation, performing serial imaging with a baseline scan performed early on before onset of severe HE may be more useful .
Brain MRI may help exclude CNS infection, brainstem stoke, Wernicke’s encephalopathy, metronidazole encephalopathy, and central pontine myelinolysis not visible on CT and should only be pursued if there is a high index of suspicion. If clinically unstable and MRI is necessary, the patient should be monitored by intensive care unit (ICU) clinicians throughout image acquisition.
8.13 Pharmacologic Treatment Options
8.13.1 Outline of management of HE in ALF
Identify and treat cause of ALF to minimize further injury
- 2.Identify risk factors for mortality and IH (Table 8.6) and evaluate candidacy for liver transplant if high riskTable 8.6
Risk factors associated with intracranial hypertension in ALF
Risk factors of IH
Possible mechanisms and rational
1. Meets Kings college Criteria
Correlates with severity of liver injury, luxury cerebral perfusion due to inflammation
Neurotoxic effects of plasma ammonia
• Predicts IH with specificity of 84% and a sensitivity of 60%
3. Plasma ammonia level >200 μmol/L 
Neurotoxic effects of plasma ammonia
4. Partial Pressure of ammonia or unionized ammonia (pNH3) 
Neurotoxic effects of plasma ammonia
5. Sustained elevation on plasma ammonia levels
Neurotoxic effects of plasma ammonia
6. Acute renal failure requiring CRRT 
i) Volume overload impeding venous return. ii) Severe acidosis iii) Decreased clearance of ammonia and glutamine.
7. Young age (<35 years) 
Limited intracranial space with limited age related atrophy
8. Vasopressor use 
i) Inflammation and multi-organ failure causing vasogenic CE from luxury cerebral. ii) Volume overload due to excessive volume resuscitation
9. Severity of Organ failure (SOFA score) 
i) Inflammation and multi-organ failure causing vasogenic CE from luxury cerebral. ii) Volume overload due to fluid resuscitation and oliguric renal failure iii) Decreased ammonia clearance with renal failure
• Predicts IH with specificity of 62% and a sensitivity of 94%
- 3.Elect neuromonitoring strategy
Invasive—intracranial monitoring devices
Noninvasive—GCS, neuro checks, pupillary exam, serial brain imaging, transcranial Doppler (TCD), jugular bulb oxymetry, optic nerve sonography
- 4.Initiate neuroprotective strategies to delay development of CE and IH
Head of bed elevation with neck in neutral position
- (b)Initiate osmotherapy with hypertonic saline or mannitol
Crucial to plan an effective osmotherapy strategy taking into account continuous reno-renal replacement therapy (CRRT)
Hypertonic saline with sodium goal of 145–150
- (d)Consider intensive care supportive strategies for multiorgan failure directed at cerebral edema (see Table 8.7)Table 8.7
Intensive care supportive strategies directed at cerebral edema in ALF
Intensive care supportive strategies
Use short acting sedatives and opiates once intubated. Propofol and low dose fentanyl are sedatives of choice. Avoid intermediate or long acting benzodiazepines.
Intubation for airway protection needs to be considered early in later stages of HE before significant aspiration and lung injury occurs.
Low tidal volume lung protective strategy to prevent ARDS. High intrathorasic pressures result in cerebral venous outflow obstruction 
High Peep → Use cautiously as very high peep can theoretically add to hepatic congestion
CO 2 goal: 30–40 mmHg → Hypercarbia causes vasodilatation
Noninvasive approach and IH suspected → Target a higher MAP goal (≥80 mmHg)
Invasive approach → Cerebral perfusion pressures (CPP) should be maintained between 50 and 60 using vasopressors 
In refractory shock → consider plasma exchange to maintain optimal CPP. Plasma exchange was associated with reduction in SIRS response, reduction in SOFA scores and decline in need for vasopressor support [63, 68]
CVP goal < 20 → Increased CVP may impede venous return from the brain . Maintain euvolemia. Consider paralysis.
Renal, acid base disorders and electrolytes
Early CRRT → To maintain euvolemia, augment ammonia clearance , correction of electrolyte and acidosis correction
Formulate strategy to maintain sodium goal (145–150) while on CRRT. Options include preparation of hypertonic prismasate or hypertonic saline infusion in post filter return arm of CRRT. Caution: Initiating CRRT with isotonic prismsate in patient with IH and induced hypernatremia can cause rebound edema from dialysis disequilibrium syndrome and precipitate brain herniation.
Hypokalemia and metabolic acidosis increases renal ammonia production.
Metabolic alkalosis promotes formation of NH3+ from (NH4+) augmenting its passage across the blood brain barrier (15, 16)
GI, liver and nutrition
Abdominal compartment syndrome may indirectly worsen ICP. Lactulose → Avoid lactulose via oral or NG route in ALF as it may cause bowel distention, worsening ileus and complicating transplant surgery. Limited evidence supporting it use in ALF. If used, it is safer to be given rectally
Avoid hypoglycemia → may add to metabolic injury to the brain. Initiate 10% or 20% Dextrose preemptively in ALF
Hematologic and immune system
Disseminated intravascular coagulation → Consider repeating head CT the patient if DIC occurs as spontaneous intracranial hemorrhages may occur.
- 5.Rescue maneuvers to control elevated intracranial pressure or refractory IH
- (a)Maintain adequate cerebral perfusion pressure
Vasopressors for shock
- (b)Increased sedation for metabolic suppression
Thiopental or Pentobarbital only as a last resort
- (c)Maximize osmotherapy with hypertonic saline
Hypertonic saline with goal sodium of 150–155
20% Mannitol with
Consider continuous neuromuscular blockade infusion for high central venous pressures (>20 mmHg) or sustained refractory ICP
Targeted temperature management (Moderate hypothermia 33–34 °C)
Consider using IV indomethacin 0.5 mg/kg bolus for refractory ICP
Correct severe acidosis with sodium bicarbonate infusions
- 6.Slow de-escalation of neuroprotective therapies post-liver transplant or in transplant free recovery
IH frequently lag behind liver recovery.
Slow normalization of serum sodium levels
Monitor for rebound edema or dialysis disequilibrium syndrome
Slow rewarming to if induced hypothermia initiated
26 year old woman with cerebral edema after acetaminophen overdose now with grade 4 encephalopathy, renal failure, NH3 of 300 mmol/L. The decision to place an intraparenchymal ICP monitor (Camino) was made given the high risk status and that patient was not a transplant candidate. She remained hemodynamically stable and on minimal ventilator settings. Intraparenchymal catheter placed after 2 units of FFP, 1 unit of Cryoprecipitate, 1 pack of platelets, and within 1 h of dosing recombinant factor VIIa which produced a resultant INR of 1.4. Platelet count was 104. Post ICP monitor placement, the patients ICP climbs from 15 to 30 mmHg and subsequently 40 mmHg despite sedation and osmotherapy with hypertonic saline.
Answer: Emergent Head CT
CT head revealed a large right intraparenchymal hemorrhage with midline shift in the region of the ICP pressure probe. Correction of coagulopathy my not be completely protective. Hyperemia of the brain likely contributes to the brisk bleeding when it does occur.
8.14 Invasive Neuromonitoring Strategy in ALF
ICP monitoring has been used to identify and treat elevated ICP aggressively especially when brain edema was the predominant cause of death [28, 70]. With improvement in ICU interventions and lower incidence of IH, the utility of invasive intracranial monitoring has been steadily decreasing. Intracranial hemorrhage from bolt placement is reported to range from 2.5% to 10% [71, 72]. While observational studies have not found overall survival advantages in those receiving ICP monitoring [73, 74], the possibility of benefit in a subset of high risk brain edema patients remains unanswered. Recombinant Factor VIIa is frequently used to help correct the coagulopathy associated with ALF before the procedure [75, 76]. When ICP monitoring is performed, the mean cerebral perfusion pressures (CPP) should be maintained between 50 and 60 using vasopressors .
8.14.1 Noninvasive Neuromonitoring Strategy in ALF
A non-invasive strategy would be reliant upon empiric use of cerebral edema-preventing interventions as listed below without the reassurance of having a pressure reading. Serial CT imaging [58, 59], Transcranial Doppler, jugular bulb oximetry, pupillometry neurological exam would be complimentary to this approach.
Transcranial Doppler ultrasound (TCD) is a non-invasive method to estimate ICP based on waveform characteristics due to resistance in cerebral blood flow in proximal cerebral circulation . Its utility in ICP detection in ALF has not been validated prospectively and has to be interpreted with caution. Trends in TCD indicating cerebral perfusion could be useful however an easy method for continuous monitoring is not yet available . Other non-invasive devices such as optic nerve sonography, technologies using near infrared spectroscopy and pupillometry have not been validated in ALF.
8.14.2 Neuroprotective Strategies in ALF
Hyponatremia can worsen cerebral edema and thus should be treated but care must be taken to avoid rapid correction.
Hypertonic saline used to prophylactically to elevate serum sodium level between 145 and 155 meq/L has been demonstrated to reduce the incidence and severity of IH in HE grade 3 and 4 patient a single center study . 30% hypertonic saline infusion titrated between 5 and 20 mL per h to maintain serum sodium levels at 145–155 mmol/L was used in this study.
Hyperosmotic agents have been traditionally used to reduce ICP. This approach may also be used in patients with elevated ICP in ALF patients . Twenty percent Mannitol in bolus doses of 0.5–1 g/Kg bodyweight can be used to reduce ICP. Serum osmolality should be monitored while on mannitol and should be kept <320 mOsm/L due to risk for renal tubular toxicity. However there is no evidence for this number . Care should be taken in patients with ARF, use of mannitol can cause volume overload from osmotic effect of drawing water from interstitial space.
Hyperventilation causes hypocapnia that induces alkalosis which in turn produces vasoconstriction and thereby a decrease in CBF and cerebral blood volume hence decreasing ICP. However, there is a serious concern of hypocapnia causing or worsening cerebral ischemia and rebound cerebral edema . Moderate short term hyperventilation reduces global cerebral blood flow without compromising cerebral oxidative metabolism . PaCO2 should be monitored and should be targeted between 30 and 40 mmHg .
Barbiturate coma may be considered with pentobarbital in selected cases . Thiopental and pentobarbital have been shown to reduce brain oxygen utilization, however, in setting of ALF, neurological assessment cannot be done due to induced coma and the half-life is prolonged due to hepatic metabolism of this drug. Pentobarbital is associated with hemodynamic instability due to the direct myocardial suppression effect and should be used and monitored with caution. Bowel dysmotility and frequent occurrence small bowel ileus is a well knows adverse effect of barbiturates. Therefore, NG lactulose should be avoided in barbiturate use altogether.
Hypothermia has been successful in decreasing ICP and has been reported to help to bridge to liver transplant [86, 87, 88]. Its use in ALF remains controversial as two studies (Temp 33–34 °C) have demonstrated both absence of benefit and harm [64, 89]. Sustained and significant reduction in plasma ammonia levels  and its utility in controlling ICP remains an attractive intervention in the ICU and perhaps should be reserved for refractory IH or refractory hyperammonemia.
Indomethacin reduced ICP by cerebral vasoconstriction in a porcine model . In a physiological study of 12 patients with ALF, IV bolus of indomethacin dose of 0.5 mg/kg reduced ICP and increased CPP without compromising cerebral perfusion. Further studies need to be performed prior to considering it for routine use. IV formulation of indomethacin is not easily available in the US.
Seizures can worsen cerebral edema and increase ICP. Since one third of patients with ALF have seizures, continuous EEG monitoring should be considered in patients who are both sedated and paralyzed . Phenytoin was shown to reduce breakthrough seizures in one small study while using it prophylactically was of no benefit in another . While phenytoin is indicated in breakthrough seizures in ALF, its side effect profile and liver induction effects should preclude its prophylactic use. It is not unreasonable to consider the use of newer antiepileptic medications with less side effect profiles and not metabolized by the liver to treat breakthrough seizures in HE.
CRRT is recommended over hemodialysis due to lower fluctuations in ICP and improved hemodynamic stability [93, 94]. CRRT is particularly effective at lowering plasma ammonia levels  and correcting hyponatremia. Appropriate consideration should be given to sodium concentration in dialysate for CRRT and intravenous hypertonic saline dosing when determining goal serum sodium level.
8.14.3 Plasma Ammonia Lowering Strategies in ALF
Ammonia plays a significant but fragmented role in the development of cerebral edema and IH. There remains a paucity of studies that show therapeutic benefit to ammonia reduction. While Lactulose and Rifaximin may offer a nominal plasma ammonia reduction effect, they are likely deficient in preventing IH in ALF. Unlike cirrhosis, ALF patients are not preconditioned to deal with hyperammonemia and are likely more susceptible to ammonia related toxicity. In practice, plasma ammonia reduction is ALF is frequently orchestrated habitually and serendipitously by using CRRT  for acute renal failure and therapeutic hypothermia  IH. Earlier use of CRRT for significant hyperammonemia, despite relatively preserved renal function, may delay the development of cerebral edema.
Over the last three decades, consistent mortality reduction in subsets of liver failure not attributable to transplantation has been evident. Death from cerebral edema and brain herniation in ALF has also significantly decreased. There is not a defining therapeutic intervention that’s has resulted in this change. Perhaps this is the net result of improved and nuanced critical care delivery and the enhanced recognition of how dysfunction of other organ systems and their respective interventions affect cerebral metabolic and hemodynamic physiology.
8.15 Review Questions
Question: Plasma NH3 level has to exceed 150 mmol/L in ALF before they are at risk of developing intracranial hypertension. True or False ?
An elevated plasma ammonia level (>150 mmol/L) in acute liver failure increases the risk of intracranial hypertension; however, a low level (<146 mmol/L) does not preclude it when associated with multiorgan failure. Vasogenic edema from hyperperfusion of the brain can occur independently of an elevated plasma ammonia levels due to the cytokine storm produced by the dying liver.
Question: Brain imaging for evaluating severe hepatic encephalopathy in patients with Acute-on-chronic Liver failure is unnecessary. True or False ?
Answer: Acute-on-chronic liver failure patients admitted with overt hepatic encephalopathy have a significantly higher short-term mortality rate and small but devastating risk of brain herniation (4%) and are at an increased risk of intracranial hemorrhage (16%). Atypical presentation of HE in these patients may warrant a head CT. In chronic liver disease without acute multiorgan failure, the yield from neuroimaging is low unless features are very atypical or there is a history of trauma.
Question: Hyperammonemia in chronic liver failure causes worsening encephalopathy leading to coma, however, the effect on the brain is always reversible with treatment. True or False ?
Ammonia is neurotoxic however patients with cirrhosis have a relative tolerance to hyperammonemia. Severe and sustained hyperammonemia in cirrhosis can cause irreversible brain injury akin to patients with urea cycle disorders. The threshold at which the injury is irreversible remain unclear. Brain MRI pattern of restricted diffusion (cytotoxic edema) in hyperammonemia states correlates in severity with plasma ammonia levels and clinical outcome.
Question: Induced hypothermia improves outcome in ALF by controlling ICP? True or False ?
Therapeutic hypothermia controls ICP, reduces plasma ammonia levels and is safe but does not confer a clear mortality benefit in acute liver failure.
Question: Monitoring and treating ICP in ALF using invasive intracranial monitoring devices result in improved control in ICP with a clear evidence of mortality benefit. True or False ?
Invasive intracranial pressure monitoring used in an estimate of 20–30% of patients with acute liver failure in North America yields a 2.5–10% risk of intracranial hemorrhage. Patient’s with intracranial monitors in a retrospective review received more interventions for ICP control and increased sedation without a discernable mortality benefit.
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