Acute liver failure (ALF) is a catastrophic condition that results in multiple organ failure. The severity of the illness and the rapidity of clinical deterioration in a previously healthy individual are alarming to patients, their families, and the health-care team. Support of the patient with ALF requires the full armamentarium of therapies available in the modern intensive care unit (ICU) and may require orthotopic liver transplantation (OLT). Survival rates have increased significantly in recent years.
Acute liver failure (the preferred term) is defined as the onset of hepatic encephalopathy (HE) and coagulopathy within 26 weeks of jaundice in a patient without preexisting liver disease. Terms that signify the duration of illness such as O’Grady’s “hyperacute” (<7 days), “acute” (7 to 21 days), and “subacute” (21 days to 26 weeks); Bernuau’s “fulminant” (<2 weeks) and “subfulminant” (2 to 12 weeks); and Mochida’s fulminant (<8 weeks) and “late onset” (8 to 24 weeks) are popular but less useful because they do not have prognostic significance distinct from the etiology.
In 2011, the American Association for the Study of Liver Diseases (AASLD) updated its position paper detailing the management of ALF. Recommendations of the U.S. Acute Liver Failure Study Group for the ICU management of such patients were published in 2007. The rarity, heterogeneity, severity, and speed of progression of ALF mean that there is a paucity of randomized controlled trials evaluating therapies, and many interventions are empiric or based on expert opinion.
Epidemiology
ALF is rare. In developed countries, an incidence of between 1 and 6 cases per million people per year has been reported. Approximately 2000 cases of ALF occur per year in the United States. Rates are probably higher in locations with high rates of infective hepatitis and/or lack of resources for treatment, but incidence data are sparse. The etiology of ALF differs depending on the geographic location. In the United States and Europe, medications are responsible for most cases. Acetaminophen is the principal culprit and accounted for 46% of the 1696 cases of adult ALF in the U.S. Acute Liver Failure Registry. As described by Larson in a prospective, multicenter study, many acetaminophen-induced cases of ALF result from unintentional acetaminophen overdose. Approximately three quarters of cases of ALF in this study were in women, and most patients were between 26 and 45 years of age. More recent estimates suggest that acetaminophen may account for up to 50% of cases of ALF. In other parts of the world, viruses (especially hepatitis A, B, D, and E) are the principal causes. There are several other causes of ALF as detailed in Table 69-1 .
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Idiosyncratic: Volatile anesthetics (especially halothane), isoniazid, rifampicin, valproic acid, nonsteroidal anti-inflammatory drugs, disulfiram |
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Clinical Presentation
Although initially a liver insult, ALF quickly becomes a multisystem disease. Loss of hepatocyte function (including host defense functions) and release of cellular debris and inflammatory mediators lead to a generalized inflammatory process. The stigma of chronic liver disease is absent. HE and coagulopathy are the characteristic features of ALF, and both may progress rapidly over days or even hours. Diagnosis of ALF is made on clinical grounds, aided by laboratory analysis. Imaging studies (e.g., hepatic ultrasound to assess the patency of the liver’s vascular supply) and liver biopsy may aid in the elucidation of the cause of ALF, but the latter is not usually performed.
Initial Assessment and Management
Most patients are initially admitted to hospital under the care of a general medical, gastroenterology or liver service. When the diagnosis of ALF has been made, a referral center with a liver transplant program should be contacted for advice on management and consideration for transfer. Some have suggested that waiting for the development of HE to diagnose ALF leads to crucial delays in treatment. When HE develops in a patient with ALF, ICU care is usually warranted because of the potential for further deterioration and the need for interventions such as intubation, mechanical ventilation, and hemodynamic support. Several institutions have developed formal protocols for management of patients with ALF. Although the utility of such protocols has not been studied in a controlled trial, they may help to ensure that all relevant aspects of the patient’s care are addressed.
Prognosis
With supportive therapy, some patients with ALF will spontaneously recover hepatic function. However, in many other cases, the patient will die without OLT. Of 1696 patients with ALF in the U.S. Acute Liver Failure Study Group dataset, overall patient survival was 71%. Although these survival figures are much better than in the pretransplantation era, ALF remains a life-threatening disease entity. The main causes of death are cerebral edema with subsequent herniation and multiple organ failure. In data reported by Lee, 660 (39%) of the 1696 patients were listed for transplantation; of these, 409 were transplanted with 371 survivors and 38 deaths. Eight hundred and twenty-six survived without transplantation, and 461 died without transplantation. In a 2-year follow-up by Fontana et al., long-term survival was significantly higher in 262 transplant recipients compared with 506 patients who survived without the need for transplantation, perhaps because of underlying comorbidities.
The timing of transplantation is crucial. Delay in listing for transplantation may result in the patient’s demise before a donor organ is found or may result in perioperative mortality. Premature listing may result in OLT being performed in patients who might otherwise have spontaneously recovered liver function. Multiple prognostic scoring systems have been developed in an effort to identify those patients at high risk of mortality. The most commonly used criteria are those developed by O’Grady and colleagues in the United Kingdom. These are commonly known as the King’s College criteria. They were developed in a cohort of 588 patients with ALF who were managed medically between 1973 and 1985. The criteria differentiate between acetaminophen-induced ALF and ALF due to other causes. They use pH, the international normalized ratio (INR), creatinine, grade of encephalopathy, age, duration of jaundice, and bilirubin level for prognostication. These criteria have been determined to have clinically acceptable specificity but more limited sensitivity. Other well-known prognostic systems include the Clichy criteria (which use encephalopathy grade, factor V concentration, and age) and the Japanese criteria (age, encephalopathy, bilirubin level, and coagulopathy). The ALF Early Dynamic (ALFED) model of Kumar et al. is a prediction model that is based on the changes in INR, serum bilirubin, arterial ammonia, and HE. A recent systematic review of prediction models noted that studies of new models were associated with methodological flaws and that the performance of any new model has yet to be evaluated prospectively in a large cohort of patients. There are insufficient data to recommend a particular scheme because none have been found to discriminate well enough and some are methodologically flawed or biased or equate transplantation with death. Table 69-2 identifies potentially helpful indicators of poor prognosis in patients with ALF. The etiology of ALF appears to be the most important factor, albeit with imperfect sensitivity and specificity.
Etiology
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Coma grade on admission
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King’s College criteria
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∗ Note that none of these factors, with the exception of Wilson disease and possibly mushroom poisoning, are either necessary or sufficient to indicate the need for immediate liver transplantation
† These criteria, in particular, have not been found to be predictive of outcome in recent analyses.
The United Network for Organ Sharing (UNOS), the donor organ allocation body in the United States, has criteria that must be satisfied before a patient may be listed as a Status IA candidate for liver transplantation (the highest priority for organ allocation). These include “acute liver failure with a life expectancy of less than seven days without a liver transplant” or “primary graft non-function, hepatic artery thrombosis and acute Wilson’s disease.”
Therapy for Specific Causes
The cause of the ALF should be sought because it will have implications for both therapy and prognosis. Diagnosis of the cause of ALF requires a detailed history, multiple serologic and imaging tests, and potentially liver biopsy.
On the basis of several studies, N -acetylcysteine (NAC) has been shown to be effective in the treatment of acetaminophen toxicity. The availability of the antidote, coupled with the frequency with which ALF is caused by acetaminophen toxicity, mean that an acetaminophen level should be drawn in every patient with ALF. Acetaminophen toxicity may be indicated by the presence of very high serum transaminases and low bilirubin levels and assays for toxicity-related serum acetaminophen-containing protein adducts. NAC should be administered even if there is doubt regarding the timing or dose of ingestion or of the plasma concentration of acetaminophen. Oral administration has largely been replaced by intravenous (IV) administration. The duration of NAC administration is determined by clinical condition rather than by time or serum acetaminophen concentration. Dosing may need to be continued beyond 72 to 96 hours. In addition to the administration of NAC, patients with known or suspected acetaminophen overdose within 4 hours of presentation should have activated charcoal administered just before starting NAC.
Drug-induced hepatotoxicity (apart from that induced by acetaminophen) is usually idiosyncratic and typically occurs during the first 6 months of therapy. Antibiotics (especially antituberculous medications), nonsteroidal anti-inflammatories, and anticonvulsants are most commonly implicated. There are no specific antidotes, but the offending agent should be identified and stopped. Herbal and nutritional supplements also may cause acute liver injury, and information regarding such supplements should be sought from the patient and family. If the cause of ALF remains indeterminate, even after liver biopsy, then further investigation of potential drug or toxin exposure should be made. In data from the U.S. Acute Liver Failure Study Group, 11% of patients with ALF were deemed to have (non-acetaminophen) drug-induced ALF, and the entity was especially common in women and minorities. Transplant-free (3-week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%.
Viral hepatitis has become a relatively infrequent cause of ALF in the United States but is more common elsewhere. Hepatitis A and B accounted for 4% and 8%, respectively, of cases of ALF in the U.S. multicenter cohort. Acute hepatitis D may cause acute liver dysfunction in a patient with preexisting hepatitis B, and hepatitis E may cause ALF in endemic areas, especially in pregnancy. Care of a patient with acute viral hepatitis is mainly supportive. Lamivudine, used in chronic hepatitis B infection, has been reported to be of use for the treatment of hepatitis B-associated ALF, although a clinical trial has not been performed. Although ALF secondary to herpes simplex or varicella zoster virus infection is rare, treatment with acyclovir has been recommended for suspected or documented cases and transplantation considered.
ALF may develop as an acute presentation of autoimmune hepatitis. Corticosteroids (prednisolone starting at 40 to 60 mg/day) are often administered in this scenario, although this practice is based on theory and case series, and, in fact, is not supported by the large retrospective analysis of Karkhanis et al. Transplantation may be required.
Acute fatty liver of pregnancy is a rare disease that may occur in the second half of pregnancy, most often in the third trimester. It resolves with delivery of the fetus. Liver transplantation has been performed for this condition but should not be necessary with early diagnosis and prompt delivery.
Wilson disease is an uncommon cause of ALF (2% to 3% of cases in the U.S. Acute Liver Failure Group cohort) but carries a grim prognosis without transplantation. Features of Wilson disease include low serum ceruloplasmin, high serum and urinary copper, hemolysis, Kayser-Fleischer rings (seen on slit-lamp examination), very low serum alkaline phosphatase and uric acid, and a bilirubin (milligram per deciliter)/alkaline phosphatase (IU/L) ratio greater than 2. Although penicillamine treatment may be used in Wilson disease, it is not recommended in the setting of ALF. Rather, other measures to reduce serum copper and prevent further hemolysis (e.g., plasmapheresis) should be initiated while the patient is waiting for an emergent liver transplant.
Amanita phalloides (mushroom) poisoning has been treated with penicillin G, NAC, and silibinin although controlled trials have not been performed, and the latter is not available as a licensed drug in the United States.
When ALF is due to an acute ischemic injury or severe congestive heart failure, treatment of the underlying cause is required, and the prognosis is related to the response to therapy of the inciting insult.
Abdominal pain, prominent hepatomegaly, and ascites may indicate acute hepatic vein thrombosis (Budd-Chiari syndrome), which may present as ALF. Liver transplantation is indicated based on high survival rates in case series, provided underlying malignancy is excluded. Malignant infiltration of the liver sufficient to cause ALF is a contraindication to liver transplantation and indicates a very poor prognosis.
Hepatic Encephalopathy
HE is one of the hallmarks of ALF. In contrast to patients with chronic liver disease, the development of HE in a patient with ALF often is associated with the development of cerebral edema and elevations in intracranial pressure (ICP). Cerebral edema is especially likely to develop in those patients with a short interval between jaundice and development of HE. Cerebral edema with subsequent herniation is the leading cause of death in patients with grade IV encephalopathy (see later) and may occur in up to 80% of these patients.
There are two main theories regarding the development of cerebral edema in ALF. It is likely that both play a role. Glutamine is the end product of brain ammonia metabolism and may accumulate in astrocytes, causing alterations in neurotransmitter synthesis, impairment of mitochondrial function, and changes in osmolality, which ultimately lead to cerebral edema. In addition, failure of cerebral autoregulation that develops as a result of ALF leads to cerebral vasodilatation with a subsequent increase in cerebral blood flow and cerebral edema. The increase in ICP leads to a decrease in cerebral perfusion pressure (CPP) and the development of cerebral ischemia. In accordance with the Monro-Kellie doctrine, cerebral edema in the fixed confines of the skull will ultimately lead to herniation and death. Hyponatremia, cytokine production, and the development of seizures each may contribute to the development of cerebral ischemia.
HE develops rapidly in patients with ALF. Alterations in mental status are initially subtle but may progress to coma. There are four grades of HE ( Table 69-3 ), and the grade of encephalopathy correlates with the development of cerebral edema and with outcome. Cerebral edema is uncommon in grade I or II, but it occurs in 25% to 35% and 65% to 75% in patients with grades III and IV encephalopathy, respectively. The prognosis worsens when grade IV encephalopathy is complicated by cerebral edema and is further worsened if renal failure is present. Furthermore, the development of infection alters the progression of HE. Although ammonia levels correlate poorly with the severity of HE, an arterial ammonia greater than 200 μg/dL within 24 hours of the development of grade III or IV HE is predictive of herniation.
| Grade | Mental Status | Tremor | EEG |
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| I | Euphoria; occasionally depression; fluctuant mild confusion; slowness of mentation and affect; untidy, slurred speech; disorder in sleep rhythm | Slight | Usually normal |
| II | Accentuation of grade I; drowsiness; inappropriate behavior; able to maintain sphincter control | Present (easily elicited) | Abnormal; generalized slowing |
| III | Sleeps most of the time but arousable; incoherent speech; marked confusion | Usually present if patient can cooperate | Always abnormal |
| IV | Not arousable; may or may not respond to painful stimuli | Usually absent | Always abnormal |
| Authors | Year | Organization | Type of Document |
|---|---|---|---|
| Lee et al. 2012 | 2012 | American Association for the Study of Liver Diseases | Position paper on the management of acute liver failure: Update |
| Stravitz et al. 2007 | 2007 | United States Acute Liver Failure Study Group | Recommendations for intensive care of patients with acute liver failure |
| Study, Year | Number of Subjects (Intervention, No Intervention) | Study Design | Intervention | Control | Outcomes |
|---|---|---|---|---|---|
| Canalese et al. 1982 | 44 patients with ALF (4 groups) | Prospective, randomized, controlled trial | Dexamethasone alone, mannitol alone, both dexamethasone and mannitol | Neither | Dexamethasone did not affect survival among patients who developed cerebral edema, survival was better in mannitol group |
| Bhatia et al. 2004 | 42 patients with ALF (22 patients given prophylactic phenytoin, 22 controls) | Prospective, randomized, controlled trial | Prophylactic phenytoin administration | Usual therapy | Similar rates of cerebral edema, need for mechanical ventilation, incidence of seizures, mortality |
| Gazzard et al. 1975 | 20 patients with acetaminophen-induced ALF (10 intervention, 10 controls) | Prospective, randomized, controlled trial | FFP 300 mL every 6 hours | Usual therapy | No difference in morbidity or mortality between intervention and control groups |
| Davenport et al. 1993 | 32 patients (12 intermittent RRT, 20 continuous RRT) | Prospective, randomized, controlled trial of patients with ALF and acute renal failure | Continuous RRT | Intermittent RRT | Patients in intermittent RRT had significantly lower cardiac indices and MAP |
| Demetriou et al. 2004 | 171 patients (85 bioartificial liver, 86 control) | Prospective, randomized, controlled, multicenter trial in patients with severe ALF | HepatAssist bioartificial liver (patients were allowed to undergo liver transplantation) | Usual therapy (including potential liver transplantation) | 30-day survival 71% for bioartificial liver vs 62% for control ( P = .26). |
| Acharya et al. 2009 | 201 patients | Prospective, randomized, placebo-controlled, trial in patients with ALF | LOLA infusions (30 g daily over 3 days) HepatAssist bioartificial liver (patients were allowed to undergo liver transplantation) | Placebo | No improvement in encephalopathy grade or survival with LOLA administration |
Treatment of Hepatic Encephalopathy and Elevated Intracranial Pressure
Grades I and II Hepatic Encephalopathy
The management of patients with HE depends on the grade. On the basis of the experience at the institution, patients with grade I HE may be managed on a general ward, with skilled nursing in a quiet environment, but in most institutions such patients should be managed in an ICU. If, and when, grade II HE develops, ICU care is indicated. A computed tomography (CT) scan of the head should be performed to exclude causes of mental status change other than HE (e.g., intracranial hemorrhage, space-occupying lesion), although transport to the CT scanner may be dangerous, especially if the patient’s airway is not protected. Although CT scans may demonstrate cerebral edema in patients with advanced HE, intracranial hypertension may not be detected.
Administration of sedatives to patients with grade I or II HE should be avoided if possible because they will confound the detection of signs that might indicate progression to the next stage of encephalopathy. Nonetheless, small doses of short-acting antipsychotics (e.g., haloperidol, benzodiazepines, or dexmedetomidine) may be required to control agitation.
On the basis of a belief that ammonia plays a role in the pathogenesis of cerebral edema in patients with ALF, lactulose has been administered to patients with HE. In a study by Alba, it was associated with a small increase in survival time but no difference in the severity of encephalopathy or overall outcome. The AASLD position paper recommends that “in early stages of encephalopathy, lactulose may be used either orally or rectally to effect a bowel purge, but should not be administered to the point of diarrhea, and may interfere with the surgical field by increasing bowel distension during liver transplantation.” Nonabsorbable antibiotics (rifaximin neomycin) also are not proven to be of use in ALF, and neomycin carries a risk of nephrotoxicity.
Grades III and IV Hepatic Encephalopathy
A patient who progresses to Grade III HE requires endotracheal intubation for airway protection. The choice of sedative or induction agents to be administered before intubation is left to the discretion of the practitioner because there are no studies to demonstrate the advantage of one regimen over another in this circumstance. It is intuitive that a drug regimen that minimizes the risk of increasing ICP should be used. Therefore propofol is a reasonable choice in this situation. If a muscle relaxant is used, then a nondepolarizing neuromuscular blocker (e.g., cisatracurium) offers some advantages over succinylcholine in terms of its effect on ICP.
Intracranial Pressure Monitoring
The use of ICP monitoring devices in ALF is subject to ongoing debate. Proponents of ICP monitoring argue that such monitoring will allow rational use of the therapies detailed below. Others suggest that the risks of monitoring outweigh its value. The U.S. Acute Liver Failure Study Group has provided data on ICP monitoring in patients with ALF. In the most recent data evaluating 629 patients with ALF, ICP monitoring was used in 140 patients (22%). Compared with controls, patients with ICP monitoring were younger and more likely to be on renal replacement therapy (RRT). Hemorrhagic complications were rare. Half of those for whom ICP data were available had elevated ICP with associated increased mortality. Overall 21-day mortality was similar in patients with ICP monitors (33%) and controls (38%; P = .24). When stratifying by acetaminophen status and adjusting for confounders, however, CP monitor placement did not affect 21-day mortality in patients with acetaminophen-induced ALF but was associated with increased 21-day mortality in ALF of other cause.
The performance of a randomized clinical trial to answer the question of whether ICP monitoring should be used would require a relatively large number of patients and has not been performed thus far. The AASLD position paper recommends that “intracranial pressure monitoring is recommended in ALF patients with high grade hepatic encephalopathy, in centers with expertise in ICP monitoring, in patients awaiting and undergoing liver transplantation.”
The risks of ICP monitoring include bleeding and infection. The former is especially worrisome in these coagulopathic patients. The ICP monitoring device of choice has traditionally been an epidural catheter. These have relatively low associated risks for intracranial hemorrhage but may be less accurate than other devices. Subdural or intraparenchymal monitors provide improved reliability at the cost of increased bleeding risk. Coagulopathy needs to be treated before placement of an ICP monitor, and newer agents for the treatment of coagulopathy (see later) may alter the threshold for placement of such devices. Definitive recommendations for INR or platelet count are not available.
There are insufficient data to recommend the use of transcranial Doppler or jugular venous bulb oximetry in patients with ALF.
Maintenance of Cerebral Perfusion Pressure
CPP is mean arterial pressure (MAP) minus ICP. The management goal for patients with cerebral edema is to limit ICP and to maintain CPP. Targets for CPP are subjects of debate, but a goal ICP less than 25 mm Hg and a CPP more than 60 mm Hg seem reasonable. A CPP greater than 70 mm Hg may be of further advantage if that level can be achieved. An ICP greater than 40 mm Hg and a prolonged period of time with a CPP less than 50 mm Hg are strongly associated with poor neurological recovery in patients with ALF, although the data are not sufficient to contraindicate OLT. It may be necessary to augment MAP to attain and maintain a satisfactory CPP (see the later section on hemodynamic support ). Systemic hypertension may be treated with conventional agents such as labetalol or hydralazine. Continuous infusions of nicardipine offer some theoretical advantage over the traditionally used sodium nitroprusside.
Control of Elevations of ICP in Patients with Grade III or IV HE
General Measures: Patients with elevated ICP (defined as an ICP >20 to 25 for more than 1 minute or a CPP <50) should be managed in a quiet environment. Head elevation to 20 to 30 degrees and avoidance of obstruction to venous return (e.g., head rotation, tight endotracheal tube ties) are recommended. Endotracheal tube suctioning should be kept to a minimum, and consideration should be given to administration of a bolus of a sedative agent such as propofol or lidocaine before suctioning. Hypoxemia and hypercapnia will increase ICP, and every effort should be made to avoid these.
Sedation and Analgesia: Patients in grade III or IV HE should be sedated as one measure to control ICP. Because of its rapid onset and offset (even in patients with liver disease), propofol seems an excellent choice for sedation to control ICP in patients with ALF. Wijdicks and Nyberg reported the use of propofol in seven patients with ALF who had ICP monitors in situ. At a median dose of 50 μg/kg/min, propofol alone appeared to control ICP, although the study was observational and there were several confounders.
The induction of a “barbiturate coma” by administration of pentobarbital or sodium thiopental has been used to treat refractory intracranial hypertension in ALF, although studies are uncontrolled. Forbes and colleagues administered thiopental to patients with ALF, refractory intracranial hypertension, and poor prognosis and demonstrated reductions in ICP. Side effects are numerous and include hemodynamic compromise and apnea.
Patients receiving infusions of propofol or barbiturates may require pressor support to maintain optimum hemodynamics.
Opiate infusions typically are used to treat discomfort and as adjunctive sedative agents. Fentanyl may be a better choice than morphine or meperidine because the last two are longer acting and have active metabolites that may accumulate in hepatic or renal dysfunction.
Mannitol: Mannitol is the only therapy proven in a controlled trial to reduce intracranial hypertension and improve survival in patients with ALF. Canalese and colleagues randomized 44 patients with ALF to receive mannitol (1 g/kg as required), dexamethasone (32 mg IV then 8 mg IV every 6 hours), both drugs, or neither drug for the treatment of elevated ICP. Dexamethasone did not affect survival, but among patients who developed cerebral edema, those who received mannitol had significantly better survival than those who did not. The dose of mannitol has not been definitively established, and boluses of between 0.25 and 1 g/kg have been used, although doses on the lower end of this range are associated with fewer adverse effects. Limitations to the use of mannitol include the development of acute renal failure or hyperosmolality (serum osmolality > 320 mOsm/L). The prophylactic administration of mannitol in ALF has not been studied.
Hypertonic Saline: Murphy et al. performed a randomized trial of the use of 30% (hypertonic) saline to maintain serum sodium concentrations between 145 and 155 mEq/L in patients with ALF and encephalopathy. They demonstrated that induction and maintenance of hypernatremia can reduce the incidence and severity of intracranial hypertension. A survival benefit was not demonstrated, and the role of prophylactic hypertonic saline remains unproven, but its use is recommended by the AASLD “in patients at highest risk of developing cerebral edema.” Theoretically, and on the basis of literature in the neurosurgical population, hypotonic solutions and hyponatremia should be avoided because of the risk of worsening cerebral edema.
Treatment of Fever: Fever exacerbates intracranial hypertension in patients with ALF, and measures to maintain normothermia, including cooling blankets and fans, should be used in the febrile patient (see the later discussion on therapeutic hypothermia ). Nonsteroidal anti-inflammatory drugs and acetaminophen are relatively contraindicated because of the potential for nephrotoxicity and further hepatotoxicity, although their use has not been studied extensively in this population and they have been used to treat fever in patients with ALF.
Hyperventilation: Hyperventilation to a partial pressure of carbon dioxide in arterial blood (Pa co 2 ) of less than 30 mm Hg causes cerebral vasoconstriction and rapidly reduces ICP in patients with cerebral edema. Prophylactic hyperventilation, however, did not reduce the incidence of cerebral edema in a randomized controlled trial of 20 patients with ALF. Furthermore, marked hypocapnia (to a Pa co 2 ≤ 25 mm Hg) or sustained hypocapnia may cause cerebral ischemia. Accordingly, the use of therapeutic hyperventilation is reserved for situations in which life-threatening cerebral edema is present and has proven refractory to other measures. Use of hyperventilation in this circumstance should be temporary—for at most a few hours. Maintenance of a Pa co 2 between 30 and 40 mm Hg is a reasonable goal.
Seizure Prophylaxis: The development of seizures will markedly increase cerebral oxygen requirements, increase ICP, and may cause or worsen cerebral edema. Subclinical seizure activity was noted in 30% of patients with ALF studied by Ellis in a clinical trial. The AASLD position paper recommends that phenytoin be given for control of seizures, although supporting data are scarce. Benzodiazepines also may be administered, for both their antiseizure and sedative properties, but their metabolism and clearance are greatly decreased in liver failure. Prophylactic IV phenytoin was shown to reduce the incidence of seizures in this group of 42 patients, but the beneficial effects of phenytoin could not be documented in a confirmatory study. The use of prophylactic phenytoin is not supported by current evidence. Electroencephalography should be performed in grade III or IV HE if myoclonus is present, if a sudden unexplained deterioration in neurologic status occurs, or when barbiturate coma is being used for management of cerebral edema.
Indomethacin: Tofteng administered bolus doses of indomethacin to a series of 12 patients with ALF and cerebral edema and demonstrated a reduction in ICP and an increase in CPP. Further data are awaited.
Nonabsorbable disaccharides, benzodiazepine receptor antagonists, or dopaminergic agonists have not been proven to be beneficial for the treatment of HE according to systematic reviews of the literature.
A randomized placebo-controlled trial of l -ornithine l -aspartate (LOLA), a drug that facilitates the detoxification and excretion of ammonia, failed to demonstrate a decline in arterial ammonia or an improvement in survival.
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