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General Management Concerns
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Because ALF often involves the rapid deterioration of mental status and the potential for multiorgan failure, patients should be managed in the intensive care unit. Table 38–2 outlines general treatment recommendations for intensive care management of patients with ALF. For patients not at a transplant center, the possibility of rapid progression of ALF makes early consultation with a transplant facility critical. Accordingly, plans for transfer to a transplant center should begin in patients with any abnormal mentation.
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Early institution of antidotes or specific therapy may prevent the need for liver transplantation and reduce the likelihood of poor outcome. N-acetylcysteine (NAC) is the antidote for acetaminophen-induced acute liver failure, but some data suggests intravenous NAC improves transplant-free survival in non–acetaminophen-induced liver failure, particularly in those patients in early stage. Other measures appropriate for specific causes of ALF are described in detail later in this chapter.
Jalan R. Acute liver failure: current management and future prospects.
J Hepatol. 2005;42(Suppl):S115–S123.
[PubMed: 15777566]
Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.
Gastroenterology. 2009;137:856–864.
[PubMed: 19524577]
Polson J, Lee WM. American Association for the Study of Liver Diseases. AASLD position paper: the management of acute liver failure.
Hepatology. 2005;41:1179–1197.
[PubMed: 15841455]
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Management of Common Complications
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Neurologic Complications
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Patients with grade I–II encephalopathy (Table 38–3) should be transferred to a liver transplant facility and listed for transplantation. Sepsis, gastrointestinal bleeding, hypoglycemia, hypoxemia and electrolyte abnormalities can worsen encephalopathy. Consider a brain-computed tomography (CT) scan to rule out other causes of decreased mental status. Stimulation and overhydration can cause elevations in intracranial pressure (ICP) and should be avoided. Unmanageable agitation may be treated with short-acting benzodiazepines in small doses, but may mask the severity of encephalopathy, limiting its prognostic value. Lactulose can be considered at this stage, but abdominal distention should be assessed at regular intervals, and the dose of lactulose should be titrated to avoid intravascular depletion. A report from the ALFSG on 117 patients suggests that use of lactulose in the first 7 days after diagnosis is associated with a small increase in survival time, but with no difference in severity of encephalopathy or in overall outcome.
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For patients who progress to grade III–IV encephalopathy, intubation for airway protection is generally required. Many centers use propofol for sedation because it may reduce cerebral blood. The head of the bed should be elevated to 30 degrees, and electrolytes, blood gases, glucose, and neurologic status monitored frequently.
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The cause of intracranial hypertension in ALF is probably multifactorial, combining cytotoxic brain edema due to an increase in cerebral blood volume and cerebral blood flow due to inflammation and toxic products of the diseased liver. Cerebral edema inside the cranial vault raises ICP and decreases cerebral perfusion assessed by cerebral perfusion pressure (CPP; defined as mean arterial pressure minus intracranial pressure).
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Factors that increase ICP need to be avoided, including high positive end-expiratory pressure, frequent movements, neck vein compression, fever, arterial hypertension, hypoxia, coughing, sneezing, seizures, head-low position, and respiratory suctioning.
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Evidence of increased ICP includes unequal pupil size and lack of pupillary reaction to light. Patients with cerebral edema may have systemic hypertension and bradycardia (Cushing reflex), increased muscle tone followed by decerebrate rigidity and posturing, abnormal papillary reflexes (usually dilation), and finally brainstem respiratory patterns and apnea. Brain herniation from elevated ICP is the immediate cause of death in 35% of patients with ALF, and 15–20% of patients listed for transplantation die from increased ICP. Cerebral edema is rarely seen in patients with grade I–II encephalopathy but increases to 65–75% in patients with grade IV coma and is the leading cause of death in these patients.
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Seizure is common in patients with ALF, although presentation is often subclinical and likely due to use of sedatives and paralytics in intubated patients. Seizures aggravate intracranial hypertension and should therefore be promptly controlled with phenytoin. Small clinical trials using prophylactic phenytoin have shown no mortality benefit and unclear impact on cerebral edema or prevention of seizures.
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The use of ICP monitoring in patients with ALF is common but not universal. Clinical signs of elevated ICP are not always present, and neurologic changes such as papillary dilation or decerebrate posturing are often present only late in the course. The risks of ICP monitoring in ALF patients include bleeding and infection, with subdural and intraparenchymal monitors demonstrating greater reliability but increased rates of complications when compared with epidural catheters. A survival benefit with the use of ICP monitoring has not been shown.
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The goal is to maintain ICP below 20 mm Hg and CPP above 70 mm Hg. Evidence of elevated ICP such as pupillary abnormalities, decerebrate posturing, or monitoring suggesting ICP above 20–25 mm Hg and CPP below 50–60 mm Hg, should prompt intervention.
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Interventions may include support of systemic blood pressure to maintain adequate CPP or the use of mannitol, which in doses of 0.5–1 g/kg has been demonstrated to decrease cerebral edema in the short term and improve survival. The efficacy of mannitol in patients with ICP may be affected by acute renal failure and oliguria. The dose may be repeated as needed as long as serum osmolality has not exceeded 320 mOsm/L. In order to be able to use mannitol repeatedly, fluid can be taken off with hemofiltration, which by itself reduces ICP. Prophylactic administration of mannitol is not indicated.
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Hyperventilation has also been shown to cause quick reductions in ICP, but the effect is short-lived and therefore may be of therapeutic benefit only in situations of life-threatening intracranial hypertension to prevent herniation.
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Barbiturate agents such as thiopental or pentobarbital may be considered when severe intracranial hypertension does not respond to other measures.
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Other therapies are being explored but currently lack adequate supporting data to recommend use, including indomethacin, hypothermia, and hypertonic saline.
Detry O, De Roover A, Honore P, et al. Brain edema and intracranial hypertension in fulminant hepatic failure: pathophysiology and management.
World J Gastroenterol. 2006;12:7405–7412.
[PubMed: 17167826]
Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management.
Semin Liver Dis. 2003;23:271–282.
[PubMed: 14523680]
Jalan R, Olde Daminck SW, Deutz NE, et al. Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure.
Transplantation. 2003;75:2034–2039.
[PubMed: 12829907]
Jalan R, Olde Daminck SW, Deutz NE, et al. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension.
Gastroenterology. 2004;127:1338–1346.
[PubMed: 15521003]
Murphy N, Auzinger G, Bernal W, et al. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure.
Hepatology. 2002;39:464–470.
[PubMed: 14767999]
Wijdicks EF, Nyberg SL.
Propofol to control intracranial pressure in fulminant hepatic failure.
Transplant Proc. 2002;34:1220–1222.
[PubMed: 12072321]
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Cardiovascular Complications
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Increased cardiac output and low systemic vascular resistance are characteristic of ALF. Pulmonary artery catheterization should be considered to monitor volume status. Hypotension should be treated preferentially with fluids, but systemic vasopressor support with agents such as epinephrine, norepinephrine, or dopamine should be used if fluid replacement fails to maintain mean arterial pressure of 50–60 mm Hg. Vasoconstrictive agents (especially vasopressin) should be avoided. Relative adrenal insufficiency occurs frequently in patients with ALF, and may contribute to cardiovascular collapse. Moderate doses (200–300 mg/day) of hydrocortisone have been shown to improve the vasopressor response to norepinephrine in hypotensive patients with sepsis and ALF.
Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group.
Crit Care Med. 2007;35:2498–2508.
[PubMed: 17901832]
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Pulmonary Complications
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Pulmonary edema and pulmonary infections are commonly seen in patients with ALF. Mechanical ventilation may be required. However, positive end-expiratory pressure can worsen cerebral edema and decrease hepatic blood flow.
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Coagulopathy and Gastrointestinal Bleeding
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Impaired hepatic synthesis of clotting factors, increased consumption of factors, low-grade fibrinolysis, and intravascular coagulation are typical of ALF. Thrombocytopenia is common and may also be dysfunctional. The prophylactic correction of INR with fresh frozen plasma is not recommended, and replacement therapy is recommended only in the setting of hemorrhage or prior to invasive procedure. Vitamin K (5–10 mg subcutaneously) should be given to treat an abnormal prothrombin time, regardless of whether there is poor nutritional status. Administration of recombinant factor VIIa has shown promise; however, this treatment approach requires further study. The use of gastrointestinal hemorrhage prophylaxis with a proton pump inhibitor is recommended.
Munoz SJ, Reddy KR, Lee WM and the Acute Liver Failure Study Group. The coagulopathy of acute liver failure and implications for intracranial pressure monitoring.
Neurocrit Care. 2008;9:103–107.
[PubMed: 18379899]
Shami VM, Caldwell SH, Hespenheide EE, et al. Recombinant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy.
Liver Transpl. 2003;9:138–143.
[PubMed: 12548507]
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Prevention of renal failure by ensuring adequate systemic blood pressure, treating infections, and avoiding nephrotoxic agents is important. Intravascular volume deficits are often present on admission and volume replacement is required. Acute renal failure may occur due to dehydration, hepatorenal syndrome, or acute tubular necrosis. Renal failure may be even more common with acetaminophen overdose or other toxic ingestions due to direct nephrotoxicity causing acid-base disturbances and lactic acidosis. Prompt fluid resuscitation with crystalloids for low arterial pressure, or colloids in pre-hepatorenal syndrome along with midodrine and octreotide, have been suggested. If renal dysfunction, fluid balance, and metabolic derangements necessitate renal replacement, continuous therapies such as continuous venovenous or arteriovenous hemofiltration should be used as they cause less fluctuation in hemodynamics and ICP than intermittent hemodialysis.
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Nutrition, Electrolytes, and Metabolic Derangements
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ALF is a high catabolic state, and adequate nutrition is essential. Caloric goal for patients should be approximately 25–30 kcal/kg/d. In patients with grade I or II encephalopathy, enteral feeding should be initiated early. Parenteral nutrition should be used only if enteral feeding is contraindicated as it increases the risk of infection. Severe restriction of protein is not beneficial; 60 g/day of protein is generally reasonable. Fluid replacement with colloid (eg, albumin) is preferred rather than crystalloid (eg, saline); all solutions should contain dextrose to maintain euglycemia.
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Multiple electrolyte abnormalities are common in ALF. Correction of hypokalemia is essential as hypokalemia increases renal ammonia production, potentially exacerbating encephalopathy. Hyponatremia is a poor prognostic indicator, and the desirable levels are above 125 mEq/L. Hypophosphatemia is especially common in patients with acetaminophen-induced ALF and in those with intact renal function. Hypoglycemia occurs in many patients with ALF and is often due to depletion of hepatic glycogen stores and impaired gluconeogenesis. Plasma glucose concentration should be monitored and hypertonic glucose administered as needed.
Schilsky ML, Honiden S, Arnott L, Emre S. ICU management of acute liver failure.
Clin Chest Med. 2009;30(1):71–87.
[PubMed: 19186281]
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Bacterial and fungal infections are common in ALF, with one study demonstrating culture-proven infection in 80% of ALF patients. Infection remains one of the leading causes of mortality in patients with ALF. Defective cellular and humoral immunity as well as presence of indwelling catheters, coma, broad-spectrum antibiotics, and medications that suppress immunity all predispose to infection. Localizing symptoms of infection such as fever and sputum production are frequently absent, and the only clues to an underlying infectious process may be worsening of encephalopathy or renal function. There must be a low threshold for obtaining frequent cultures (blood, urine, and sputum), chest radiographs, and paracentesis. Bacteria that enter through the skin, such as streptococci and staphylococci, tend to predominate, and therefore broad spectrum antibiotics (quinolones or third-generation cephalosporin) are generally used. Fungal infections, particularly in the setting of broad-spectrum antibiotics, are also common, and disseminated fungemia is a poor prognostic sign. Aggressive surveillance is essential, as prophylactic antibiotics have shown little benefit, though empiric antibiotic administration can be considered where infection or the likelihood of impending sepsis is high.
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Table 38–2 summarizes these and other strategies in the ICU management of ALF patients.
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Liver Transplantation
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The advent of transplantation has changed survival from as low as 15% in the pre transplant era to more than 60% today. Liver transplantation is indicated for many patients with ALF, and survival rates of 56–90% can be achieved. In addition to transplantation, better critical care and the trend toward more benign causes, such as acetaminophen, all contribute to improved survival rates. Spontaneous survival is now around 45%.
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The application of transplantation among patients with ALF remains low, suggesting that the full potential of this modality may not be realized. Timely availability of an allograft is one of the major factors determining transplant outcomes. In the largest U.S. study, only 29% of patients received a liver graft, while 10% of the overall group (one fourth of patients listed for transplantation) died on the waiting list. Other series have reported death rates of those listed for transplant as high as 40%.
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Current United Network for Organ Sharing (UNOS) criteria for priority (Status 1) listing are (1) onset of any degree of hepatic encephalopathy within 8 weeks of onset of acute liver injury; (2) absence of preexisting liver disease; (3) life expectancy of less than 7 days; and (4) in the intensive care unit (ICU) requiring either mechanical ventilation, renal dialysis, or with severe coagulopathy (INR 2.0).
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In the ALFSG, the transplantation rate was higher in the groups with lower short-term spontaneous survival, making overall survival similar in all groups: acetaminophen, 73%; drug induced, 70%; indeterminate group, 64%; and other causes, 61%. Causes of death for the 101 patients who died within the 3-week period included cerebral edema, multiorgan failure, sepsis, cardiac arrhythmia or arrest, and respiratory failure. The median time to death after admission was 5 days.
Brown RS Jr, Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States.
N Engl J Med. 2003;348:818–825.
[PubMed: 12606737]
Farmer DG, Anselmo DM, Ghobrial RM, et al. Liver transplantation for fulminant hepatic failure: experience with more than 200 patients over a 17-year period.
Ann Surg. 2003;237:666–675.
[PubMed: 12724633]
Lee WM, Squires RH, Jr, Nyberg SL, et al: Acute liver failure: Summary of a workshop.
Hepatology. 2008;47:1401–1415.
[PubMed: 18318440]
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Liver Support Systems
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Clinical experience with bioartificial systems is mostly confined to small numbers of patients in uncontrolled trials. One systematic review of 12 randomized trials (with a total 483 patients) assessing artificial and bioartificial support systems for acute or acute-on-chronic liver failure as a "bridge" to transplantation showed no significant effect on mortality compared with standard medical therapy. Currently, available liver support systems are not recommended for the treatment of ALF.