Liver disease results in approximately 35,000 deaths each year, making it the 12th leading cause of death in the United States.1 Patients suffering from ALF or consequences of chronic liver disease are among the sickest in the hospital. These patients often develop problems that require critical care, and physicians should be knowledgeable about the various complications of liver disease that can be encountered in the intensive care unit (ICU).
There are an estimated 2000 cases of acute liver failure (ALF) annually, which accounts for 0.1% of all deaths in the United States. Approximately 6% to 7% of all LTs performed in the United States are secondary to ALF.2,3
ALF is defined as the rapid and severe development of liver dysfunction, marked by encephalopathy and coagulopathy with an elevated prothrombin time (PT) or international normalized ratio (INR), in an individual without a prior history of cirrhosis or liver disease. The exceptions to this definition are in patients who have had previously undiagnosed hepatitis B virus (HBV) infection, hepatitis D virus (HDV) infection with underlying chronic HBV infection, autoimmune hepatitis, or Wilson disease. In these patients, underlying cirrhosis may be present, provided the disease has been recognized for less than 26 weeks.
ALF can be subcategorized by the interval between the development of jaundice and onset of encephalopathy. Common classification cutoffs are: hyperacute (< 7 days), acute (8-28 days), and subacute (28 days-26 weeks). This classification can be clinically useful as cerebral edema is common in hyperacute and acute liver failure whereas complications of portal hypertension are more commonly seen in subacute liver failure.
In the United States, drug-induced hepatitis, especially acetaminophen overdose is the most common cause of ALF in adults. Other causes of ALF are listed in Table 37–1.
Table 37–1Causes of acute liver failure. ||Download (.pdf) Table 37–1 Causes of acute liver failure.
Acute viral hepatitis
Hepatitis A virus
Hepatitis B virus +/– hepatitis D virus
Hepatitis C virus
Hepatitis E virus
Cytomegalovirus in immunocompromised patients
Herpes simplex virus in immunocompromised patients
Sinusoidal obstruction syndrome
Ischemic (shock) liver
Acute fatty liver of pregnancy
HELLP syndrome (hemolysis, elevated liver function tests, low platelets)
Malignant infiltration of the liver
Signs and Symptoms—The symptoms of ALF may vary depending on the severity and etiology. In the case of acetaminophen toxicity, patients may present with rapid onset of abdominal pain, nausea, vomiting, and confusion, several hours after ingestion of acetaminophen. The presentation of ALF due to other etiologies can be more insidious. Patients may present with nonspecific symptoms such as malaise, fatigue, or subtle changes in personality and behavior. New-onset ascites, pruritus, or asymptomatic jaundice can also be seen.
Encephalopathy is a prerequisite to the diagnosis of ALF, and the degree of encephalopathy may be variable from mild to severe (Table 37–2).
Table 37–2Grades of hepatic encephalopathy.4 ||Download (.pdf) Table 37–2 Grades of hepatic encephalopathy.4
|I ||Changes in behavior minimal change in level of consciousness |
|II ||Gross disorientation, drowsiness, possibly asterixis, inappropriate behavior |
|III ||Marked confusion, incoherent speech, sleeping most of the time but arousable to vocal stimuli |
|IV ||Comatose, unresponsive to pain, decorticate or decerebrate posturing |
Patients with encephalopathy grade I may have mild asterixis whereas patients with grades II, III, or IV may have overt asterixis or clonus on physical examination. The development of encephalopathy grade III and IV usually heralds the development of cerebral edema and increased intracranial pressure (ICP).
Laboratory Findings—Laboratory testing will reveal a prolonged PT and increased INR greater than 1.5, not correctable by the administration of intravenous (IV) or subcutaneous (SC) vitamin K. Bilirubin and aminotransferase levels are often elevated. Elevated serum creatinine (Cr) and blood urea nitrogen (BUN) levels can be seen with concurrent acute kidney injury (AKI). AKI occurs in up to 80% of patients with ALF and can occur secondary to hypovolemia, sepsis, or acute tubular necrosis (ATN).5 ATN can occur as a result of severe hypotension or, in the case of acetaminophen ingestion, as a result of direct tubular toxicity.6 Acidosis is common in ALF as a result of the body's inability to clear lactic acid in the setting of severe hepatic necrosis and concurrent AKI. The severity of laboratory abnormalities and encephalopathy can be used to help predict patient outcomes (Table 37–3).
Table 37–3Predictors of poor outcome in patients with acute liver failure (King's College Criteria).7 ||Download (.pdf) Table 37–3 Predictors of poor outcome in patients with acute liver failure (King's College Criteria).7
Acetaminophen-induced acute liver failure
Arterial pH < 7.30 (irrespective of grade of encephalopathy) or
A combination of encephalopathy grade III or IV, PT > 100 s (INR > 6.5), and serum Cr > 3.4 mg/dL
Nonacetaminophen-induced acute liver failure
ALF is a medical emergency with high rates of multisystem organ failure and high mortality without appropriate management. Only 40% of patients diagnosed with ALF have spontaneous recovery.8 Thus, all patients presenting with ALF should be managed in a center with an active liver transplant program.
Patients with grade I encephalopathy can be managed with care in a general medical ward, provided that they undergo frequent neurologic checks (every 2 hours) to identify signs of progression to higher grades of encephalopathy. Grade II encephalopathy and higher should be managed in the ICU.
Specific etiologies of ALF may have specific management options that can help avoid LT and decrease mortality (Table 37–4). Of special note, N-acetylcysteine, which is the antidote of choice for acetaminophen toxicity, may also be of benefit in other forms of ALF. The administration of NAC has been shown to increase transplant-free survival in patients with grade I and II encephalopathy, presenting with nonacetaminophen ALF.9
Table 37–4Specific etiologies of acute liver failure and potential treatments. ||Download (.pdf) Table 37–4 Specific etiologies of acute liver failure and potential treatments.
|Acetaminophen toxicity ||N-acetylcysteine |
|Mushroom toxicity (Amanita phalloides) ||Penicillin G or silymarin |
|Valproate ||Carnitine |
|Hepatitis B virus +/– hepatitis D virus ||Antiviral nucleo(s)tide (eg, entecavir, tenofovir, lamivudine, adefovir, telbivudine) |
|Herpes simplex virus ||Acyclovir |
|Budd-Chiari syndrome ||Transjugular intrahepatic portosystemic shunt placement, surgical shunt placement, or thrombolysis |
|Autoimmune hepatitis ||Prednisone |
|Wilson disease ||Usually will require liver transplantation but plasma exchange can be a temporizing measure |
|Acute fatty liver of pregnancy ||Expedited delivery of the fetus |
Regardless of the etiology, supportive measures remain essential in the management of ALF patients.
Cerebral Edema and Intracranial Hypertension—Cerebral edema leading to intracranial hypertension remains the major cause of mortality in patients presenting with ALF. The pathogenesis of cerebral edema is not clearly understood in ALF and likely is secondary to multiple factors including the breakdown of the blood-brain barrier, neurotoxin release, and resultant osmotic disturbances. The predictors of cerebral edema include high-grade encephalopathy (grade III/IV) and increased arterial ammonia concentration (> 200 μmol/L).10,11
Simple interventions may be beneficial to reduce intracranial hypertension in patients with grade III/IV encephalopathy. Tracheal intubation with sedation, elevation of the head to 30°, minimization of painful stimuli, and control of arterial hypertension should be initiated universally. A quiet environment should be maintained to reduce external stimuli, and premedication should be given prior to tracheal suctioning or patient positioning to minimize changes in ICP.
The use of ICP monitoring devices in ALF is controversial, and its use is largely dependent on local practices. The decision to place an ICP monitoring device should be made after discussion with the ICU, transplant hepatology, and neurosurgery teams.
If the patient does develop increased ICP as evident by direct ICP monitoring or neurologic examination (pupillary abnormality or decerebrate posturing), further measures to reduce ICP should be initiated. The goal of therapy is to reduce the ICP to below 20 to 25 mm Hg while maintaining cerebral perfusion pressure (CPP) above 50 to 60 mm Hg.
Mannitol causes osmotic diuresis and has been shown to decrease ICP. Its use has been associated with improved survival in ALF.12,13 Patients can be given bolus doses of mannitol to decrease ICP, provided that serum osmolality does not exceed 320 mOsm/L. The use of mannitol is limited in the setting of volume overload and renal failure. Hypertonic sodium chloride (30% normal salaine [NS]) can also be considered to maintain serum (Na) levels of 145 to 155, to prevent a rise in ICP.14
Hyperventilation to reduce Paco2 quickly lowers ICP via vasoconstriction and decrease in cerebral blood flow. However, this effect is short lived and does not adequately lower ICP long term.15
Seizure—Seizure activity in patients with ALF is common but difficult to detect in intubated and sedated patients. Seizures should be treated promptly as seizure activity can acutely increase ICP and cause cerebral edema.16
Infection—Infection is a major contributor to mortality in patients presenting with ALF. All patients with ALF are at increased risk for bacterial and fungal infections. Common sites of infection include the respiratory tract, urinary tract, and blood. Routine surveillance cultures should be obtained from the sputum, urine, and blood along with chest radiograph to detect infections early, as severe sepsis increases mortality as well as precludes potential LT. Prophylactic antibiotic use is controversial but can be considered in patients with severe encephalopathy. Empiric antibacterial and antifungal antibiotics should be started if patients present with worsening hypotension or renal failure, as early signs of infection.
Coagulopathy—Coagulopathy, marked by prolonged PT and INR, is universal in patients presenting with ALF. PT/INR is one of the predictors of outcomes in ALF (see Table 37–3), and thus, empiric correction of PT/INR with fresh frozen plasma (FFP) should be held unless patients have signs of overt bleeding or are in need of an invasive procedure. If a patient has signs of overt bleeding or is in need of an invasive procedure, such as ICP monitoring device placement, FFP and/or recombinant human factor VIIa can be used to help reverse the coagulopathy. However an increasing body of data suggests that routine correction of PT/INR is not necessary prior to percutaneous vascular access procedures, paracentesis, and other nonneurosurgical procedures in patients with liver disease.
Renal Failure—AKI can be seen in 55% to 80% of patients presenting with ALF.5,17 Maintenance of euvolemia is critical and determination of preload responsiveness via echocardiography should be considered to manage volume status. Nephrotoxic drugs such as aminoglycosides should be avoided and renal replacement therapy (RRT) may need to be initiated in setting of worsening renal function. If patient requires RRT, continuous rather than intermittent RRT is recommended to avoid large fluid shifts that may impact ICP.
Cardiovascular Support—ALF is characterized by high cardiac output with low systemic vascular resistance secondary to decreased clearance of vasoactive metabolites. Vasopressor drugs may be required to maintain adequate systemic mean arterial pressure (MAP) and CPP.
Respiratory Failure—Acute respiratory distress syndrome (ARDS) occurs in one-third of patients presenting with ALF and can cause significant hypoxemia that requires low tidal volume and high positive end-expiratory pressure (PEEP) to achieve adequate tissue oxygenation.10 The lowest possible PEEP should be used as high PEEP ventilation can exacerbate cerebral edema and hepatic congestion.
Nutrition—Hypoglycemia is common in ALF due to severe hepatic necrosis that impairs glycogenolysis and gluconeogenesis. Frequent serum glucose monitoring should be instituted, and profound hypoglycemia should be managed with continuous glucose infusion. Hyperglycemia should be avoided as it may contribute to poor ICP control.
Owing to the catabolic state of ALF, enteral nutrition should be initiated as early as possible.
Liver Transplantation—Liver transplantation remains the only definitive therapy for patients who are unable to achieve timely regeneration of liver mass to maintain life. Spontaneous survival rate from ALF is 40%, as compared to posttransplantation survival rate of greater than 80%.8 Although imperfect, the King's College Criteria is most often used to help triage those that may benefit from LT (see Table 37–3).
Early involvement of a multidisciplinary LT team is essential to determine if a patient is a suitable organ recipient, medically, psychologically, and socially. Timely evaluation for LT is essential; as high as 37% of patients die despite being listed for LT due to the shortage of available organs.18
Cirrhosis is characterized by progressive hepatic fibrosis and represents the final, common pathway of a variety of chronic liver diseases (Table 37–5). With progressive injury to the liver, patients with cirrhosis can have consequences of liver dysfunction, such as jaundice, coagulopathy, and hypoalbuminemia. Scarring and architectural distortion of the liver lead to portal hypertension with resultant ascites, variceal formation, hepatic encephalopathy (HE), thrombocytopenia, and renal failure. These consequences of cirrhosis lead to increased morbidity and mortality, especially in patients with high Model for End-Stage Liver Disease (MELD) scores. Liver transplantation remains the only definitive treatment for complications from cirrhosis.
Table 37–5Causes of liver fibrosis and cirrhosis. ||Download (.pdf) Table 37–5 Causes of liver fibrosis and cirrhosis.
Drug and toxins
Right-sided heart failure
Sinusoidal obstruction syndrome
Hereditary hemorrhagic telangiectasia
Acute Gastrointestinal Bleeding From Esophageal Varices
Gastroesophageal varices form as a result of increased portal pressures and occur in about 50% of patients with cirrhosis. Usually, the hepatic venous pressure gradient (HVPG) must be at least 12 mm Hg for varices to form.19 Hemorrhage from varices occurs at a yearly rate of 6% to 76%, depending on the size of the varices and the severity of the underlying liver disease.20 The mortality of patients presenting with variceal hemorrhage approaches 20%.21 Early identification of gastroesophageal varices is important as prophylaxis with beta-blockade or endoscopic variceal ligation (EVL) decreases the risk of variceal hemorrhage.
Signs and Symptoms—Patients with hemorrhage from gastroesophageal varices present with hematemesis or melena. Patients often present with hemodynamic instability marked by tachycardia and hypotension.
Laboratory Findings—Anemia occurs frequently, but a decrease in hemoglobin level may not be detected early in the course of hemorrhage.
Similar clinical presentation can be seen in other etiologies of upper gastrointestinal hemorrhage such as from peptic ulcer diseases, Mallory-Weiss tears, and Dieulafoy lesions.
Patients with suspected acute variceal hemorrhage should be managed in an ICU. The need for airway protection with tracheal intubation should be assessed early. Adequate peripheral venous access should be obtained and volume resuscitation started to maintain hemodynamic stability. Transfusions with FFP and platelets should be considered in patients with severe coagulopathy and thrombocytopenia.
However, red blood cell transfusion should be used cautiously in patients with suspected variceal hemorrhage. Overtransfusion may propagate bleeding due to increased portal pressures. Prospective, randomized data suggest that restricting red blood cell transfusions improves outcomes in acute variceal hemorrhage. A restrictive transfusion strategy (transfusion when hemoglobin falls below 7 g/dL) compared to a liberal transfusion strategy (transfusion when hemoglobin falls below 9 g/dL) resulted in lower rates of death, rebleeding, and adverse events.22 Of note, the study excluded patients presenting with massive exsanguination. In these patients, it may be prudent to initiate volume resuscitation and transfuse blood products to help maintain hemodynamic stability prior to obtaining hemoglobin levels.
Vasoactive Drugs—Vasoactive drugs should be started as soon as a variceal hemorrhage is suspected. These drugs can temporize bleeding prior to more definitive treatment modalities.
The somatostatin analog, octreotide, causes splanchnic vasoconstriction and is a safe pharmacologic therapy to decrease portal pressures. It is given as a bolus infusion of 50 μg IV followed by a continuous infusion at 25 to 50 μg/h. Meta-analysis suggests improved outcomes with the use of octreotide as compared to placebo when paired with EVL.23
Despite routine outpatient use to reduce portal pressures, beta-blockers should not be used during acute hemorrhage as it decreases systemic blood pressure and blunts physiologic increase in heart rate associated with acute hemorrhage.
Antibiotic Prophylaxis—Cirrhotic patients with upper gastrointestinal bleeding have high rates of developing severe bacterial infections including spontaneous bacterial peritonitis (SBP), urinary tract infection, and bacteremia. Trials have shown that short-term antibiotic prophylaxis given at presentation and continued for 7 days improves infection rates as well as survival after variceal hemorrhage.24 Oral norfloxacin 400 mg twice daily or IV ceftriaxone 1 g once daily can be used.
Endoscopic Treatment—For suspected variceal hemorrhage, early endoscopy (< 12 hours after presentation) is recommended. For esophageal variceal hemorrhage, EVL should be used to control bleeding. When combined with pharmacologic therapy, EVL is effective in controlling bleeding in up to 90% of patients.25
Gastric type varices are seen in about 20% of patients with portal hypertension.26 Active gastric variceal hemorrhage has a poor response to EVL and sclerotherapy. Endoscopic variceal obturation with tissue adhesive such as N-butyl-cyanoacrylate, isobutyl-2-cyanoacrylate, or thrombin is more effective, controlling bleeding in 90% of patients.27 However, variceal obturation is not routinely practiced, and its use may be limited by local expertise.
In those with early rebleeding, repeat attempt at endoscopic intervention can be considered. If hemorrhage cannot be controlled, balloon tamponade can be used as a temporizing measure to control bleeding in 80% of patients.28
Shunt Procedures—The placement of a transjugular intrahepatic portosystemic shunt (TIPS) is an effective way to decrease portal pressures and is now widely used as an option to control refractory bleeding from esophageal and gastric type varices. A reduction in HVPG to below 12 mm Hg or a reduction in HVPG greater than 20% from baseline appears to effectively eliminate the risk of rebleeding.29,30 Caution should be taken in patients with heart failure, pulmonary hypertension, and intrinsic renal failure as the extra shunting of blood volume into the systemic circulation may not be handled appropriately in these patients. By increasing shunting from the portal vasculature to the systemic vasculature, TIPS placement may also worsen symptoms of HE. Elective TIPS procedure in a patient with a high MELD score (> 18) is relatively contraindicated as it may precipitate worsening liver dysfunction.31 The presence of hepatocellular carcinoma (HCC) is also a relative contraindication to TIPS placement as it may promote vascular seeding.
Surgical shunt procedures such as portacaval, mesocaval, and splenorenal shunt procedures have been used successfully to control refractory bleeding but have now fallen out of favor given the effectiveness of the TIPS procedure.
Balloon-Occluded Retrograde Transvenous Obliteration—Balloon-occluded retrograde transvenous obliteration (BRTO) is a technique that is widely used in Asia to treat gastric varices. BRTO is a fluoroscopically guided transcatheter procedure used to introduce sclerosants into gastric varices. It relies on the presence of a gastrorenal or gastrocaval shunt to access the varices. If the appropriate shunt is identified on cross-sectional imaging, BRTO can be considered to treat gastric varices in select centers with local expertise.32 BRTO has been shown to control bleeding in up to 88% of patients with active gastric variceal bleeding.33
Ascites is the pathologic accumulation of fluid in the peritoneal space, and cirrhosis accounts for 85% of cases.34 Ascites is one of the most common complications of cirrhosis, developing in 58% of patients within 10 years of the diagnosis of cirrhosis.35 Patients who develop ascites have a 1-year mortality of 15% and 5-year mortality of 44%.36
Symptoms and Signs—Patients presenting with large-volume ascites complain of increased abdominal girth and discomfort. Nausea, early satiety, and anorexia are common symptoms. Clinical examination can reveal a distended abdomen with shifting dullness and the presence of fluid waves.
Laboratory Findings—A diagnostic paracentesis should be performed in all patients presenting with new-onset ascites. Inspection of the ascitic fluid can help determine the etiology of ascites. A serum albumin-ascites gradient (SAAG) should be calculated in all new-onset ascites. A SAAG greater than or equal to 1.1 g/dL has a 97% sensitive for the detection of portal-hypertensive ascites.34 A protein level greater than 2.5 g/dL in the ascitic fluid can further help classify portal-hypertensive ascites into the category of cardiac ascites.37
Diuretics—Minimal ascites can be managed effectively with a Na-restricted diet (2 g/d). In patients with moderate ascites, the addition of diuretic regimen consisting of a loop diuretic (eg, furosemide) and aldosterone inhibitor (eg, spironolactone) is effective in controlling ascites in 90% of patients.38 The combination works better than either diuretic alone and helps to maintain normokalemia. Initial dose of 40 mg daily of furosemide and 100 mg daily of spironolactone is usually well tolerated by patients. If serum Cr and electrolytes remain stable, the diuretic dose can be increased in a step-wise fashion up to 160 mg daily for furosemide and 400 mg daily for spironolactone. Daily weight loss of 1 kg until euvolemia is appropriate.
Paracentesis—In less than 10% of patients, ascites can be refractory to Na-restricted diet and diuretics. These patients may benefit from serial large-volume paracentesis (LVP). LVP is safe and effective in removing large amounts of ascites at one time. Even in the absence of urine output, ascites can be well controlled when performed every other week.39 LVP can significantly increase plasma renin and serum Cr; however, this effect can be tempered by the use of albumin replacement.40 Typically 25% IV albumin at a dose of 8 g per 1 L of ascites removed is given to attenuate the electrolyte and fluid shift changes seen after LVP.
Shunt Procedures—An alternative to serial LVP is the TIPS procedure. Several trials have shown improved control of ascites in the TIPS group as compared to serial LVP.41,42 However, TIPS should be placed with extreme caution in patients with severe HE, heart failure, pulmonary hypertension, intrinsic renal disease, HCC, and high MELD scores (> 18).
Spontaneous Bacterial Peritonitis
SBP is an infection of the ascitic fluid without a surgically treatable intra-abdominal source and most commonly occurs as a complication of ascites from advanced cirrhosis.43 SBP is diagnosed in 12% of hospitalized patients with cirrhosis and ascites.44 In-hospital mortality of SBP can be up to 33%.45
Symptoms and Signs—Patients may present with fever and abdominal tenderness, but often the presenting symptoms may be subtle, such as confusion and fatigue. Approximately 13% of patients with the diagnosis of SBP have no signs or symptoms of infection.46 SBP should be suspected in any patients presenting with signs of hepatic decompensation in the setting of cirrhosis and ascites.
Laboratory Findings—Diagnosis of SBP is by the presence of an ascitic fluid absolute polymorphonuclear leukocyte (PMN) count greater than 250 cells/mm3.47 Gram stain and cultures should be sent from the ascitic fluid, but the yield can be low in identifying the offending organism. Concurrent blood culture can increase the diagnostic yield of identifying an organism.
As PMN count results are available more quickly than culture results, patients with ascitic PMN counts greater than 250 cells/mm3 should be treated with broad-spectrum antibiotics. The 3 most common organism isolates are Escherichia coli, Klebsiella pneumoniae, and Streptococcal pneumoniae. Empiric treatment with third-generation cephalosporin such as ceftriaxone or cefotaxime appears to be effective in covering 95% of cases.48 After antibiotic sensitivities of the organism are obtained, the antibiotic coverage can be adjusted accordingly. If no clinical improvement is seen in 48 hours, a repeat diagnostic paracentesis should be considered to assess the PMN response and to document sterility of the ascites.
Hepatorenal syndrome (HRS) is the development of renal dysfunction in the setting of cirrhosis and ascites. Progressive portal hypertension and splanchnic vasodilatation are followed by fall in systemic vascular resistance. Relative renal hypoperfusion occurs with resultant vasoconstriction of the renal circulation and drop in glomerular filtration rate (GFR).
HRS is divided into 2 types. Type I is characterized by the rapid and progressive impairment in renal function with associated oliguria. Without treatment, type I HRS is uniformly fatal. Type II HRS develops more slowly and is marked by relatively mild reduction in renal function. Typically, patients with type II HRS present with diuretic-resistant ascites. The diagnostic criteria for HRS are listed in Table 37–6.
Table 37–6Diagnostic criteria for the hepatorenal syndrome.49 ||Download (.pdf) Table 37–6 Diagnostic criteria for the hepatorenal syndrome.49
Presence of cirrhosis with ascites
Serum creatinine greater than 1.5 mg/dL
No improvement of serum creatinine (decrease to level < 1.5 mg/dL) after at least 2 ds with diuretic withdrawal and volume expansion with albumin (1 g/kg of body weight per day up to a maximum of 100 g/d).
Absence of shock
No current or recent treatment with nephrotoxic drugs
Absence of parenchymal kidney disease as indicated by proteinuria greater than 500 g/d, microhematuria (> 50 red blood cells per high-power field), and/or abnormal renal ultrasonography
Signs and Symptoms—Patients present with signs of progressive renal failure. Volume overload can be seen with oliguria. Signs of uremia may be present, including progressive confusion.
Laboratory Findings—Serum Cr is greater than 1.5 mg/dL with concurrent BUN elevation. Urinary Na concentration less than 10 mEq/L and serum Na concentration less than 130 mEq/L are often seen in patients with HRS.
Other causes of AKI should be excluded, as patients with cirrhosis may be especially susceptible to prerenal azotemia and ATN. Patients should be questioned about recent use of nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs or aminoglycosides.
Pharmacologic Therapy—Initial management of patients presenting with renal failure should be volume resuscitation to exclude prerenal azotemia. Albumin (1 g/kg of body weight per day, up to a maximum of 100 g/d) should be given. If no improvement in renal function is seen and HRS is suspected, an attempt at pharmacologic therapy should be attempted.
Terlipressin is the drug studied most extensively to treat HRS. In combination with albumin, it has been shown to have 50% efficacy in reversing HRS.50 Terlipressin is currently not available in the United States.
The combination of oral midodrine (7.5-12.5 mg 3 times daily), SC octreotide (100-200 μg 3 times daily), and IV albumin may be utilized as an alternative to terlipressin. The combination appears to be effective in lowering serum creatinine and 30-day mortality.51
For patients in the ICU, albumin and continuous IV norepinephrine can be attempted to reverse type I HRS.52
Renal Replacement Therapy—More often, patients with type I HRS are unresponsive to pharmacologic therapy, and RRT is required to manage electrolyte imbalance and volume overload. Expedited LT evaluation should be performed in these patients, as the development of type I HRS is a predictor of poor outcome.
Hepatic encephalopathy is a reversible impairment in neuropsychiatric function associated with hepatic dysfunction. The exact pathophysiology of HE in chronic liver disease remains unclear, but a combination of elevated ammonia level along with alteration in blood-brain barrier leads to changes that activate inhibitory neurotransmitters (gamma-aminobutyric acid, [GABA], serotonin) and impair excitatory neurotransmitters (glutamate, catecholamine). Overt HE is present in 30% of patients with cirrhosis and is a frequent reason for hospital admissions.53 Common precipitants of HE are listed in Table 37–7.
Table 37–7Precipitating factors of hepatic encephalopathy. ||Download (.pdf) Table 37–7 Precipitating factors of hepatic encephalopathy.
Portal decompression procedure
Portal vein or hepatic vein thrombosis
Symptoms and Signs—Patients can present with varying degrees of neuropsychiatric dysfunction, ranging from subtle cognitive deficits to overt coma (see Table 37–2).
Laboratory Findings—Patients will have abnormal liver function tests, reflective of their underlying liver disease. Electrolyte disturbances may be seen that can precipitate HE. Patients may have elevated arterial and venous ammonia levels. However, an elevated ammonia level is not required to make the diagnosis of HE, and the level often does not correlate with the degree of encephalopathy.
General supportive care should be provided to patients presenting with HE. Appropriate triage of patients should be made depending on the severity of encephalopathy. Patients with agitation or confusion may need close supervision to avoid injury. In patients presenting with grade IV encephalopathy, observation in an ICU may be appropriate with consideration for tracheal intubation for airway protection.
The treatment of HE begins with the correction of any underlying, precipitating factors, including infection, bleeding, dehydration, electrolyte abnormality, and renal dysfunction.
Treatment with lactulose, a synthetic disaccharide, is the mainstay of therapy for overt HE despite limited evidence from randomized trials.54 Lactulose is metabolized by the colonic flora and lowers colonic pH. The resultant pH favors the formation of nonabsorbable NH4+ from NH3, thus reducing plasma ammonia concentration. Lactulose also works to clear ammonia via its osmotic laxative effect. Oral or rectal lactulose can be given for acute overt HE until mental status improves. Once HE resolves, the drug dose can be titrated to achieve 2 to 3 soft bowel movements per day.
In combination with lactulose, rifaximin, a nonabsorbable antibiotic, has been shown to maintain remission of HE.55 Rifaximin 550 mg twice daily or 400 mg 3 times daily is effective in controlling HE with minimal reported adverse effects. Other antibiotics such as metronidazole and neomycin have been used for HE. However, concern for long-term side effects including neuropathy for metronidazole and ototoxicity for neomycin has limited their chronic use in HE.
l-Ornithine l-aspartate, zinc, branched-chain amino acids, flumazenil, and sodium benzoate have all been used with variable success in HE and may be options in the setting of brittle encephalopathy.