Intensive Management of Hepatic Failure

Mary E. Rinella, M.D.1 and Arun Sanyal, M.D.2

ABSTRACT

A substantial number of patients with liver failure are admitted to the intensive care unit; thus a thorough understanding of the prevention and treatment of complications in such patients is imperative. The management of liver failure is demanding and often involves the combined efforts of many specialists. Critically ill patients with hepatic failure encompass a broad spectrum of disease, ranging from acute liver failure in a patient with no prior history of liver disease, to acute on chronic liver failure. The initial assessment and management of acute liver failure are reviewed with an emphasis on the prevention and treatment of brain edema in the pretransplant setting. The current treatment of compli- cations resulting from decompensated chronic liver disease such as portal hypertensive bleeding; infection, renal failure, and hepatic encephalopathy are then discussed.

KEYWORDS: Liver failure, cerebral edema, portal hypertension, management

The management of liver failure is demanding plantation. Although ALF remains one of the most acute and often involves the combined efforts of many special- serious illnesses, thoughtful intensive management can ists. Critically ill patients with hepatic failure encompass optimize the patient’s chances for spontaneous hepatic a broad spectrum of disease, ranging from acute liver regeneration or a successful liver transplant.3 When failure in a patient with no prior history of liver disease, possible, etiology-targeted therapy should be initiated to end-stage decompensated cirrhosis. Both sides of this (Table 1). The goal of management should be focused spectrum present clinical challenges that involve many on the prevention of systemic infection, multiorgan fail- organ systems. Although both sides in acute and chronic ure, hepatic encephalopathy (HE), and ultimately the liver failure can have a poor prognosis, careful and development of brain edema.4–6 At this time liver trans- comprehensive intensive care can improve outcome and plantation is the only definitive therapy for those who bridge eligible patients to liver transplantation. Because fulfill criteria for poor prognosis7–9 (Table 2). The acute and chronic liver failure are very distinct clinical challenge to the clinician is selection of patients for entities, they will be discussed separately. transplant that have low likelihood of spontaneous sur- vival but are not too ill to benefit from transplantation. The principles of management of ALF are reviewed here: ACUTE LIVER FAILURE Acute liver failure (ALF) is a rapidly progressive, often fatal syndrome characterized by jaundice, encephalop- athy, and coagulopathy leading to multiorgan failure in a INITIAL EVALUATION AND MANAGEMENT patient with no prior history of liver disease.1,2 In recent Early diagnosis and identification of the subject that is years, advancements in supportive care have improved unlikely to improve spontaneously constitute a critical survival and provided a more effective bridge to trans- first step in the management of ALF. The initial triage

1Division of Hepatology, Northwestern University, Chicago, Illinois; Non-pulmonary Critical Care: Managing Multisystem Critical Ill- 2Division of Gastroenterology, Department of Internal Medicine, ness;GuestEditor,CurtisN.Sessler,M.D. Virginia Commonwealth University, Richmond, Virginia. Semin Respir Crit Care Med 2006;27:241–261. Copyright # 2006 Address for correspondence and reprint requests: Arun Sanyal, by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, M.D., Division of Gastroenterology, Department of Internal Med- NY 10001, USA. Tel: +1(212) 584-4662. icine, Virginia Commonwealth University, MCV Box 980341, DOI 10.1055/s-2006-945528. ISSN 1069-3424. Richmond, VA 23298-0341. E-mail: [email protected]. 241 242 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

Table 1 Etiology-Targeted Therapy and an accurate history cannot be overemphasized be- Etiology Potential Therapies cause both treatment and prognosis are significantly affected by the underlying etiology. A detailed account TOXIC of the psychiatric history, including suicidal ideation Acetaminophen N-acetyl cysteine and family support, is essential to assess suitability Amanita poisoning Penicillin and silibinin for transplantation. The timing of the psychiatric evalua- VIRAL tion is of particular importance, given the rapid deterio- Herpes simplex virus Acyclovir ration in mental status that occurs in such patients. Acute heptatitis B Antivirals? METABOLIC Wilson’s disease Transplant DISEASE-TARGETED THERAPY Autoimmune hepatitis Corticosteroids A thorough discussion of the differential diagnosis of VASCULAR ALF is beyond the scope of this review; however, Acute Budd-Chiari syndrome Directed thrombolysis, Table 1 provides a summary of common etiologies of transjugular intrahepatic ALF for which potential therapies exist. Only acetami- portosystemic shunt nophen will be discussed in more detail because it is the PREGNANCY most common etiology of liver failure in the United Acute fatty liver of Urgent delivery States and has an effective antidote. pregnancy/HELLP HELLP, hemolysis elevated liver enzymes low platelets. Acetaminophen of a patient with acute liver injury to an intensive care Idiopathic and drug-related liver injuries are the most unit (ICU) is based on the presence of altered mental common causes of ALF in the United States.10 Of the status and the degree of coagulopathy. It is imperative drug-related causes, acetaminophen overdose is the most toadmitmostsubjectswithacuteliverinjurywithan common cause of ALF in the United Kingdom and international normalized ratio (INR) > 1.5 and all United States. Overdose can be either intentional or subjects with mental status changes. Rapid deteriora- unintentional.11–13 The patient, family, and close contacts tion can occur and is often irreversible in the patient must be questioned about regular alcohol use, dieting, diet with ALF. It is therefore imperative that decisions pills, medications, or recent illness that may have resulted regarding prognosis and appropriateness for liver trans- in poor nutrition. These factors greatly affect toxicity plant be made early, and potentially suitable patients either through upregulating cytochrome p450 (alcohol should be referred to a liver transplant center early in and other drugs) promoting the formation of toxic inter- the evaluation process. mediates, or through glutathione depletion. Such details The management of patients in liver failure are important because as little as 2.6 to 4.0 g of acetami- requires a multidisciplinary approach involving hepatol- nophen can lead to liver failure in this setting.14–17 ogists, transplant surgeons, intensivists, and other sub- It is worth noting that, at the time of presenta- specialists. The importance of a thorough physical exam tion, a patient with acetaminophen-induced liver failure may have undetectable blood levels of acetaminophen. Table 2 King’s College Criteria for Acute Liver Failure This is particularly true when the toxicity manifests itself Acetaminophen induced several days after ingestion of acetaminophen for ther- apeutic purposes in a susceptible subject. However, in Arterial blood pH < 7.3 (regardless of degree of the majority of cases, detectable acetaminophen levels encephalopathy) are present at the time of presentation. When acetami- If no acidosis then all three of the below criteria: nophen overdose is confirmed, N-acetylcysteine (NAC) Prothrombin time > 100 seconds must be initiated in a timely manner, ideally within Serum Creatinine > 2.5 mg/dL 16 hours of ingestion, to have a significant impact on Grade 3 or 4 encephalopathy Nonacetaminophen induced survival. NAC decreases injury through enhancement of glutathione synthesis resulting in less formation of Prothrombin time > 100 seconds acetaminophen’s hepatotoxic intermediate.18,19 Even if If prothrombin time < 100 seconds, then any of the below the patient is delayed in reaching the hospital or the criteria (regardless of degree of encephalopathy): diagnosis is not forthcoming, there is evidence that late Drug-induced, non-A, non-B, halothane hepatitis administration of NAC can be beneficial.20 NAC may Time from jaundice to encephalopathy > 7 days also improve outcome through its effects on micro- Age < 10 or > 40 years circulatory function. A large multicenter study (the Prothrombin > 50 seconds ALF study group) is currently addressing the utility of Bilirubin > 17.5 mg/dL NAC in nonacetaminophen-induced ALF. INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL 243

Table 3 Acute Liver Failure: General Management Guidelines On Admission Daily Tid Hourly If Indicated

Monitoring IV access, CVP and arterial Blood sugar Mental status Mechanical intubation, line, Foley catheter ICP monitoring

Thorough history Interview family members and physical

Laboratories Liver panel, renal panel, Basic laboratories, AFP, Blood gas Changes in CBC, PT, Hep A,B,C arterial ammonia ICP monitor serologies, HSV, CMV, (or more if mental EBV, ceruloplasmin, ANA, status deteriorating anti-sm Ab, SPEP, phosphate, HIV, acetaminophen factor V level level, toxicology screen, cosyntropin stimulation test, TSH, blood type, blood cultures

Imaging US with Doppler Head CT for neurological changes or suspected edema

Directed therapy where indicated Drugs, cooling for cerebral edema AFP, alpha feta protein; ANA, antinuclear antibody; anti-sm Ab, antismooth muscle antibody; CBC, complete blood count; CMV, cytomegalo- virus; CT, computed tomography; CVP, central venous pressure; EBV, Epstein-Barr virus; HSV, herpes simplex virus; HIV, human immunode- ficiency virus; ICP, intracranial pressure; IV, intravenous; PT, prothrombin time; SPEP, serum protein electrophoresis; TSH, thyroid stimulating hormone; US, ultrasound.

MONITORING AND GENERAL GUIDELINES overload and pulmonary edema, especially when renal Acute hepatic dysfunction has profound effects on many function begins to deteriorate. Alternate approaches in- organs. Therefore, one must remain cognizant of the clude the use of plasmapheresis where a volume of plasma ramifications of specific therapies on other systems. The equal to the amount infused is removed to prevent mental status must be documented several times daily, in volume overload. Recently, recombinant factor VII addition to frequent assessment of hepatic synthetic (40 mg/kg) has been used in conjunction with FFP to function and blood glucose (Table 3). Although a liver rapidly correct coagulopathy prior to either intracranial biopsy may be helpful if the diagnosis is in question, it can pressure monitor or central line placement in patients be unreliable in predicting outcome and is risky given the with ALF.25 presence of underlying coagulopathy.21 Low serum phos- phate and elevated a fetoprotein can be encouraging signs of hepatic regeneration.22,23 In a retrospective analysis of MECHANICAL VENTILATION ALF patients, 74% of patients with phosphate levels Mechanical ventilation should be initiated once ence- < 2.5 were alive at 1 week, in contrast to none in those phalopathy deteriorates to grade 3 (West Haven cri- with a serum phosphate > 5.24 teria) to protect the airway.26,27 In addition to preventing Coagulopathy in ALF does not usually require aspiration in the patient with compromised mental status, correction unless an invasive procedure is planned or intubation and sedatives help control agitation, which can overt bleeding is present because the use of fresh frozen lead to surges in intracranial pressure. Patients with plasma (FFP) can mask deterioration of liver function. A encephalopathy beyond grade 3 are very difficult to common indication for the correction of coagulopathy manage without intubation and sedation.28 is placement of a central line. Traditionally, FFP and Sedation is best achieved with a short-acting cryoprecipitates have been used for the correction of sedative alone or in combination with a short-acting coagulopathy in subjects with ALF. This is only partially narcotic. Recent evidence supports the use of propofol effective in correcting coagulopathy and its effects are for this purpose. In a small study, propofol was given to short-lived. It is also associated with a risk of transmitting seven patients with ALF and profound encephalopathy. cytomegalovirus infection and may contribute to volume Intracranial pressure (ICP) remained normal in six of 244 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

seven patients with ALF given propofol at 50 mg/kg/ min, suggesting propofol may have independent benefi- cial effects on ICP.29 Paralytics are usually avoided because they can mask seizure activity. However, they may be used in specific cases to facilitate management when the subject does not respond appropriately to sedation. In such cases, it is imperative to consider the possibility of seizure activity if the clinical picture continues to deteriorate. H2 antagonists or proton pump inhibitors may decrease the incidence of ulcer disease in mechanically ventilated patients30; however, the theoretical risk of increasing the incidence of pneumonia has not been studied in this population.

PREVENTION AND MANAGEMENT OF COMPLICATIONS Figure 1 The effect of antibiotic prophylaxis on the prevalence of documented infection patients with acute liver failure. Circulatory Dysfunction (Adapted from Salmeron et al.47) Derangements in circulatory function manifest early in ALF and are often progressive. They are characterized by generalized vasodilation, increased cardiac output, de- respectively. These infections presented at a median of creased systemic vascular resistance, and a low mean 5, 3, and 2 days after the onset of ALF.44 arterial pressure (MAP).31–33 It is challenging to distin- Given the frequency of both gram-negative and guish this clinical picture from the hemodynamics of gram-positive infections in this population, broad spec- sepsis, particularly given that infection is common and trum antibiotic coverage should be administered avoid- often a fatal complication.34 Factors such as adrenal ing aminoglycosides due to their nephrotoxicity.34 insufficiency also complicate management by making Although no randomized controlled trials have demon- the vasculature less responsive to vasopressive agents.35,36 strated improved survival with prophylactic antibiotics, In general terms, fluids and vasopressors should parenteral antibiotics are associated with a lower inci- be used to maintain adequate cerebral perfusion pressure dence of infection46 (Fig. 1).47 Given these data, pro- (CPP) (50 mm Hg to 65 mm Hg) while avoiding phylactic broad-spectrum antibiotics seem justifiable cerebral hyperemia from hyperperfusion.37,38 Because given that uncontrolled infection in such patients is the circulatory disturbance in ALF is characterized by often catastrophic.48,49 vasodilation and increased cardiac output, norepinephr- ine is frequently the vasopressor of choice. Systemic Inflammatory Response Syndrome Even in the absence of documented infection, systemic Infection inflammatory response syndrome (SIRS) is common in Patients with ALF are particularly susceptible to severe those with ALF and is likely due to a surge of cytokine infection due to many immunological defects such as release.50 In a study from King’s College, 57% of 887 defective phagocytic function and decreased comple- patients with ALF developed SIRS. The presence of ment levels.39–42 Bacterial or fungal sepsis is a frequent SIRS on admission was independently associated with cause of death in this population. Much like other more severe illness, worsening of encephalopathy, and immunocompromised hosts, their response to infection subsequent death. In those patients that were infected is atypical in that signs such as fever or leukocytosis are (54%), mortality increased with each additional compo- absent in 30% of cases.43 Thus sepsis is both frequent nent of SIRS. At this point it remains unclear how and difficult to diagnose in subjects with ALF. In a additional infection contributes or which component of prospective study of 887 patients with ALF, one or more the observed inflammatory response originates from bacterial infections occurred in 37.8%; however, an humoral factors released by the necrotic liver.34,46,51 incidence of up to 80% has been reported.44 Of these, gram-positive cocci were the most common organisms isolated, although Escherichia coli and Klebsiella were also Adrenocortical Insufficiency frequent pathogens.45 Overall, pneumonias make up Adrenocortical insufficiency can worsen hyperdynamic 50% of bacterial infections in ALF with bacteremia cardiovascular collapse typical of ALF or septic shock.52 and urinary tract infections occurring in 20 and 25%, This should be considered when the patient fails INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL 245

Figure 2 Factors leading to the development of brain edema and potential therapeutic interventions. to respond to volume resuscitation.35 In sepsis, supra- on ICP.55,56 Moreover, intermittent hemodialysis has physiological doses of steroids in patients with adrenal been associated with increases in ICP and decreases in insufficiency have been shown to reduce vasopressor CPP, whereas the opposite has been shown in patients requirements and improve outcome.36,53 Adrenal receiving CVVH.55,57 dysfunction appears to also be prevalent in patients with ALF; 62% of patients with ALF were found to have an abnormal response to high-dose corticotrophin Hepatic Encephalopathy and the Development stimulation. The patients with pronounced hemody- of Intracranial Hypertension namic instability had more marked evidence of adrenal The development of HE and subsequent cerebral edema insufficiency, suggesting that it may contribute to the and intracranial hypertension (ICH) define prognosis in pattern of cardiovascular collapse seen in liver failure.54 patients with ALF.2,7,58 Treatment options for such The benefit of stress-dose steroids in this population patients are limited. As a result, 30% of patients needs to be tested in a randomized-controlled trial; with ALF and cerebral edema succumb to cerebral however, given these data, it is reasonable to look for herniation while awaiting an organ.7,31 Without urgent and consider treating adrenal insufficiency in patients transplantation, mortality can exceed 90% in those who with ALF. have uncontrolled ICH. The pathogenesis of cerebral edema is complex (Fig. 2). ALF leads to many hemodynamic changes, Renal Failure including impairment of cerebrovascular autoregulation Renal failure is common in those with advanced liver and blood flow. This impairment makes the standard failure and is multifactorial in etiology. Common causes assumption that CPP ¼ MAP ICP less reliable.38 of renal failure in this population include prerenal Other factors such as high arterial ammonia levels azotemia, renal ischemia, acute tubular necrosis, and contribute to brain edema through the accumulation hepatorenal syndrome. A majority of patients with of glutamine and alanine in astrocytes. In response to ALF complicated by profound hypotension and cerebral swelling, a vasodilating factor is released that leads to edema will require renal replacement therapy.31 Due to increased CBF and thus increased ICP.59 the marked vasodilation that characterizes such patients, Arterial ammonia levels > 200 mmol/L in the continuous venovenous hemofiltration (CVVH) tends to setting of ALF have been shown to herald impending be better tolerated and may have more beneficial effects cerebral herniation and poor outcome.60,61 Other 246 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

Figure 3 Proposed algorithm for the use of an intracranial pressure monitor.

markers of brain cell dysfunction and damage such as Although treatments aimed at reducing ICP can s100-b and neuron-specific enolase (NSE) have also be used without an ICP monitor, an accurate ICP been evaluated as potential predictors of impending reading permits targeted therapy to optimize CPP and herniation in the setting of ALF and acute on chronic detect abrupt surges in pressure that necessitate addi- liver failure with negative results.62 Currently, no serum tional therapy. Concomitant measurement of jugular markers of brain cell dysfunction reliably demonstrate bulb oxygen saturation,32,66 which allows measurement neurological injury and poor outcome. of brain oxygen utilization, can also be useful in the Unfortunately, it can be difficult to predict which management of these patients.32 Jugular bulb oxygen patients are likely to develop elevated ICP. Clinical signs saturation > 80% or < 60% predicts elevation in ICP 31 such as arterial hypertension, fever, and agitation can with good sensitivity and specificity. Jugulovenous O2 precede episodes of severe ICH; however, these are not saturations < 50% may herald an increase in anaerobic reliable predictors because elevated ICP is often clin- cerebral glycolysis, increased lactate:pyruvate ratio, and ically silent.63 Although a computed tomographic (CT) worsening cerebral edema.67 scan is usually used to look for cerebral edema, a normal scan does not exclude the presence of edema because its appearance on imaging may be delayed. When and in Whom to Insert an Intracranial Pressure Monitor To justify the risks of ICP monitor placement, the INTRACRANIAL PRESSURE MONITORING monitor needs to be placed under controlled circum- A significant clinical challenge in the management of stances, when increased ICP is likely to rise but before ALFisthedecisiontoplaceanICPmonitor.Thereare uncontrolled ICH and herniation occur. ICP monitor- no strict guidelines related to the use of these monitors ing should be considered for mechanically ventilated andexperienceacrossinstitutionsishighlyvariable. patients with grade 3 or 4 encephalopathy with poor Noninvasive techniques have not proven to be benefi- prognosis (Table 2) but who are otherwise good candi- cial and direct ICP monitoring is the only reliable dates for liver transplant (Fig. 3). Other predictors of modality for the measurement of ICP. The benefit increased ICP such as arterial ammonia > 150 mmol/L that can be derived from ICP monitoring is twofold. could be used to time monitor placement. In those with First, it allows for the early detection and treatment of poor prognosis without orthopedic liver transplant ICH because it can be clinically silent.63 Second, it can (OLT), ICP monitoring can guide therapy and prevent provide invaluable information about the likelihood of surges in ICH before and during OLT. neurological recovery when deciding whether to pro- ceed with liver transplantation, such as when CPP is persistently low. Sustained CPP < 40 mm Hg predicts Risks of Intracranial Pressure Monitoring a high likelihood of ischemic brain injury that typically As with all interventions, the risks of ICP monitor results in a poor neurological outcome after transplan- placement need to be balanced against the accuracy and tation.64,65 Figure 3 proposes an algorithm for the use usefulness of the information to be gained. No random- of ICP monitors in ALF. ized, controlled trial is available to compare different INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL 247 catheters in the setting of ALF. Types of catheters include induction and maintenance of hypernatremia (145 to epidural, subdural, parenchymal, and intraventricular 155 mmol/L) in patients with grade 3 or 4 encephalop- catheters. Blei et al performed a survey of transplant athy resulted in a decreased incidence and severity of centers across the United States. They estimated that ICH.72 Other techniques to reduce brain water accu- 20% of ICP monitoring resulted in intracranial bleeding. mulation through the reduction of arterial ammonia Epidural catheters had the lowest rate of bleeding com- remain under investigation.73–75 plications (3.8%) and subdural and parenchymal catheters the highest; 20% and 22%, respectively.68 A recent multi- MANNITOL center study from the ALF study group showed that ICP Mannitol administration leads to increased plasma os- monitors were only used in 92/332 patients (28%) with molality in brain capillaries, resulting in movement of ALF and severe encephalopathy; however, the frequency water out of the brain according to Starling’s law. It has of monitoring differed between centers. Ten percent had been shown to decrease episodes of cerebral edema and intracranial bleeding as a result of the ICP monitor. In result in improved survival in a cohort of patients with two of these patients, ICP monitoring was directly ALF (47.1 and 5.9%, respectively, p ¼ .008).76 Its use, associated with the patient’s death.69 Although the risk however, is limited in renal failure and can lead to a of complications is greater,70 subdural catheters give a paradoxical increase in brain swelling if osmolality is not more reliable estimate of ICP than epidural catheters.68 controlled. If more than two doses are to be used, plasma Bleeding complications can be decreased signifi- osmolality must be checked to assure that it remains cantly with the use of recombinant factor rVIIa given < 320 Osm/L. immediately before the procedure.25 The frequency of factor VII dosing was variable in this study; however, as a HYPERVENTILATION group all patients that received factor VII normalized Hyperventilation is an effective technique to decrease their prothrombin time (PT) and were able to have ICP cerebral blood flow (CBF) and ICP. It does so through monitors placed (compared with 38% in the FFP alone precapillary hypocapnic vasoconstriction and helps re- group). The ideal initial dose and subsequent doses of store CBF autoregulation.61,77–79 Although prophylactic factor VII necessitates further study.71 The data show hyperventilation appears to be ineffective in preventing that ICP monitoring can be an effective tool for manag- the development of ICH,77 it can be useful in controlling ing elevated intracranial pressure; however, ICP mon- acute surges in ICP. itors have not been shown to improve survival. Currently there is no consensus about the use of ICP monitoring or INDOMETHACIN whether the more accurate but higher-risk subdural Indomethacin leads to cerebral vasoconstriction effects catheters or the less accurate but safer epidural catheter via altering cerebral temperature and extracellular pH should be used. Individual centers will continue to use and inhibition of the endothelial cyclooxygenase path- what they are comfortable with; however, their decision way.80 Its effectiveness has been proven in an animal may be influenced by the decreased availability of epi- model81 and in a small cohort of patients with ALF.82 dural catheters. However, due to its multiple systemic side effects in patients with ALF, its routine use cannot be supported.

Prevention and Treatment of Increased THIOPENTAL SODIUM Intracranial Pressure In a small, uncontrolled study, thiopental sodium was Routine measures such as elevation of the head of the effective in reducing ICP.83 Unfortunately, its use is bed to 30 degrees,55 sedation, minimal stimulation, and associated with significant hemodynamic derangements mechanical ventilation to minimize cerebral stimulation that may necessitate escalation of vasopressor or inotropic should be adhered to whenever possible. The manage- support. Thus thiopental use should be reserved for ment should be focused on maintaining an adequate surges of ICH unresponsive to standard medical therapy. CPP (> 50 mm Hg) while minimizing elevations in ICP (< 20 mm Hg). Blood pressure should be maintained to HYPOTHERMIA achieve a CPP between 50 and 65 mm Hg. Prolonged Moderate hypothermia (32 to 33C) in animal models of CPP below 50 mm Hg in the setting of ICH or an ICP ALF has been effective in improving encephalopathy greater than 40 mm Hg is associated with poor out- and reducing brain water.84,85 Clinical studies of hypo- come.65 thermia have also shown significant reduction in ICP. Jalan et al were able to demonstrate that cooling patients HYPERTONIC SALINE with refractory ICH to 32 C decreased ICP to < 20 mm The use of hypertonic saline is thought to help restore Hg. Subsequently they demonstrated a reciprocal in- the osmotic gradient across the astrocyte membrane. A crease in ICP with rewarming.86 Since this study, the randomized, controlled trial recently demonstrated that same and other groups have also shown that moderate 248 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

hypothermia is effective in the prevention of ICH in oped thrombocytopenia; thus its use should be restricted ALF, as a bridge to transplant,87 and during liver trans- in patients with DIC.102 plantation88 to prevent surges in ICP. The mechanism of action is presumed to be multifactorial but includes reduction of CBF, cerebrospinal fluid (CSF) ammonia, LIVER TRANSPLANTATION FOR ACUTE and extracellular glutamate concentrations. Although LIVER FAILURE hypothermia may be beneficial to the brain in decreasing Because the mortality of patients with ALF is almost ICP, it also impacts coagulation and may promote universal once they meet criteria for poor prognosis infection and cardiac rhythm disturbances. It is difficult (Table 2), they receive the utmost priority. The Status to know, however, if hypothermia exacerbates such 1 classification has remained from the former process of factors because these are well-known complications of organ allocation. To receive this listing, the patient must liver failure per se. Some have raised concern that have no prior history of liver disease and fulfill criteria for hypothermia may impair hepatic regeneration and ‘‘com- ALF with poor prognosis. mit’’ patients to transplant.89,90 The degree to which Intensive medical supportive care is geared toward hypothermia influences such factors needs to be ad- the avoidance of complications that could preclude dressed in a well-designed randomized, controlled trial transplant. The decision to proceed with transplantation before its use in routine practice can be justified. is a difficult one not only from a medical management perspective but also due to the limited time available to assess the patient’s social support network, mental stabil- LIVER ASSIST DEVICES ity, compliance, and wishes. Psychiatric stability and Liver assist devices are of two general types: biological strong social support are essential to a successful trans- devices and artificial devices. Biological devices use living plant. It is imperative to accurately document active hepatocytes to replace liver function, whereas artificial drug or alcohol abuse, suicidal ideation, or history of a devices such as the molecular absorbent recirculating previous suicide attempt because these are examples of system (MARS) aim to remove injurious substances potential contraindications to transplant. from the circulation. Most of the trials in ALF have used either porcine hepatocytes [bioartificial liver (BAL) device]91 or human HepG2 cells (ELAD [extracorporeal ACUTE OR CHRONIC LIVER liver assist device]).92 A large multicenter study of BAL FAILURE—GENERAL CONSIDERATIONS in ALF resulted in no survival advantage.93 In a small Critically ill patients with cirrhosis admitted to the ICU randomized controlled trial, ELAD resulted in less have poor survival even if they survive the initial ICU severity of encephalopathy without improvement in stay. Mortality can reach 100% in cases complicated by survival.94 Overall, the data on bioartificial liver devices septic shock.103–106 Acute hepatic decompensation in a are disappointing in that they are quite costly and have patient with chronic liver disease (AoCLF) is most not resulted in improved synthetic function or survival.95 commonly precipitated by gastrointestinal bleeding or MARS removes free and albumin-bound toxins infection. As a result of this, major functions of the liver via a polysulfone membrane.96,97 In contrast to bioartifi- such as the synthesis of key proteins, detoxification, and cial devices, MARS has mainly been tested in acute on metabolic regulation are impaired to various degrees. chronic liver failure (AoCLF). Two small randomized The imbalance created by the physiological needs of the clinical trials have shown improvement in encephalop- critically ill patient and the liver’s limited ability to athy and increased survival.98,99 MARS also appears to be perform key functions leads to life-threatening compli- effective in ameliorating renal function in hepatorenal cations such as renal failure, infection, HE, cholestasis, syndrome and hemodynamics through increasing sys- ascites, and bleeding. temic vascular resistance (SVR).100 Although not a An important step in the initial management of primary end point, survival was improved in a prospec- patients with AoCLF is the identification and treatment tive, randomized, controlled trial of MARS in liver fail- of the precipitating factor that led to acute decompen- ure.99 The study was terminated prematurely due to sation. Patients admitted to the ICU with AoCLF perceived ethical considerations. Unfortunately, had as should be managed with a simultaneous multifaceted little as one or two deaths occurred in the MARS group approach that will bridge eligible patients to transplan- the difference in survival would have no longer been tation and improve short-term survival in nontransplant statistically significant. The results of this trial would candidates. have had a more profound impact if the study had achieved its targeted enrollment. A recent meta-analysis found that MARS offered no significant survival benefit PORTAL HYPERTENSIVE BLEEDING over standard medical therapy.101 MARS appears to be Portal hypertensive hemorrhage is a serious and frequent well tolerated; however, a fair number of patients devel- complication of advanced cirrhosis.107–109 Bleeding can INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL 249

Table 4 Child-Pugh Score Score Bilirubin/mmol/L Albumin/g/L INR Ascites Encephalopathy

1 < 2 > 3.5 < 1.3 Absent 0 2 2.1–3 2.8–3.5 1.3–1.5 Mild I/II 3 > 3 < 2.7 > 1.5 > Moderate III/IV The Child-Pugh score is derived from the sum of the assigned points in each category. Child-Pugh A, B, and C are defined as < 6, 7–9, and > 10, respectively. INR, international normalized ratio. originate from gastroesophageal varices, portal hyper- namic instability is often present and needs to be tensive gastropathy, or less commonly from portal col- addressed with continuous cardiac monitoring and opathy, duodenal or rectal varices. A successful outcome good intravenous access. Knowledge of the central depends on accurate diagnosis, prompt resuscitation, venous pressure is helpful to gauge the adequacy of hemodynamic support, management of complications, volume administration without overresuscitating the and control of active bleeding. Clinical factors associated patient because this can provoke more bleeding from with bleeding include deterioration of liver function, previously decompressed varices or lead to other com- portal vein thrombosis, hepatocellular carcinoma, and plications such as acute pulmonary edema.121,122 Pro- ongoing alcohol use.110 phylactic endotracheal intubation should be considered In cirrhosis, portal hypertension is the result of in the setting of significant upper gastrointestinal the combined effects of increased portal venous inflow hemorrhage prior to endoscopic intervention for airway and an increased resistance to that flow.111 The corrected protection. Figure 4 proposes an algorithm for the sinusoidal pressure gradient is inversely associated with management of AVH. risk of bleeding as well as outcome after bleeding.112–114 A hepatic venous pressure gradient (HVPG) of 12 mm Hg is a threshold value, with variceal hemorrhage Esophageal Variceal Hemorrhage occurring above this level112 and therapeutic interven- Mortality associated with AVH has improved in the tion aiming at a reduction below this value.115,116 How- past decade.123 Based on data comparing patients ever, many studies have shown that if portal pressure is presenting with AVH from 1981–82 to 1988–91, the reduced in a sustained manner by 20%, the risk of late cohort experienced a significant decline in mortal- bleeding is low (10% at 2 years), even if the HVPG ity at 30 days (20.8% vs 29.6%, p ¼ .0001) and at 6 years remains above 12 mm Hg.109,117 (69.7% vs 74.5%, p ¼ .0001). For patients who survived Acute variceal hemorrhage (AVH) occurs in 30 to the first 30 days, survival was slightly better in the late 35% of patients with cirrhosis and is associated with cohort on multivariate analysis (p ¼ .01).124 Spontane- significant mortality. A recent retrospective analysis re- ous cessation of bleeding occurs in 50% of patients; ported in-hospital, 6-week, and overall mortality rates of however, 60% of these patients will rebleed if there is no 14.2%, 17.5%, and 33.5%, respectively, suggesting im- intervention.120 Therapeutic options for the manage- proved therapy of AVH has impacted survival.118 One- ment of variceal hemorrhage include pharmacological year survival following a variceal bleed greatly depends on therapy (somatostatin, octreotide, vasopressin, or terli- the severity of liver disease assessed by the Child-Pugh pressin), endoscopic therapy (endoscopic band ligation classification (Table 4). Mortality after a variceal hemor- or sclerotherapy), balloon tamponade, transjugular in- rhage is 5% and 50% in Child-Pugh A and C cirrhotic trahepatic portosystemic shunt (TIPS) or surgical patients, respectively,119 and 70% of those that survive shunts (Fig. 4). Pharmacological treatment is effective will rebleed.110,120 A hepatic venous pressure gradient and should be initiated on admission to the ICU. > 20 mm Hg after an acute bleed is an independent Although studies have shown some drugs to be as predictor of poor outcome. Such measurements may be effective as endoscopic therapy,125,126 this is controver- useful to assess prognosis and tailor therapy.114 sial; thus we recommend endoscopic intervention in The management of patients with gastroesopha- addition to pharmacotherapy for the control of variceal geal varices involves (1) prevention of the initial bleed hemorrhage. (primary prophylaxis is beyond the scope of this review), (2) management of the acute bleed, and (3) prevention of rebleeding (secondary prophylaxis). Gastric Variceal Hemorrhage Gastric varices represent a less frequent, but important source of bleeding in patients with portal hypertension. Variceal Hemorrhage—General Considerations They are present in up to 57% of patients with esoph- Acute hemorrhage typically presents with hematemesis ageal varices secondary to portal hypertension.127 Less with or without melena or hematochezia. Hemody- commonly, they are found in the absence of esophageal 250 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

Figure 4 Proposed algorithm for the management of acute variceal bleeding.

varices.128 If isolated gastric varices are noted imaging and cardiac and pulmonary vascular glue emboli.136–138 must be performed to exclude splenic vein thrombosis Recently, pilot studies have found thrombin injections because this is managed with splenectomy. In 117 to be another promising approach.139 Yet another way patients with fundal varices, the size of the vessels, the to control bleeding gastric varices is with special de- presence of red spots, and the degree of liver decom- tachable endoscopically placed snares.140,141 Although pensation were predictors of bleeding.129 Although there is limited experience with the technique in the bleeding from gastric varices is less common than bleed- United States, the Japanese report success with balloon- ing from esophageal varices, bleeding episodes are often occluded retrograde transvenous obliteration (B-RTO) more severe and carry a higher mortality.128,130–132 of isolated gastric varices.142,143 Unfortunately, most of The management of bleeding from gastric vari- these modalities are not routinely available in the ces differs from that of esophageal varices. Although United States. gastric varices in continuity with esophageal varices can The first-line approach to the control of actively be managed by endoscopic band ligation, isolated bleeding fundic varices is balloon tamponade. The air- varices in the fundus of the stomach are not amenable way must be protected when this approach is taken. This to either sclerotherapy or band ligation.133 However, is, however, a temporizing measure and such varices have numerous reports have documented the efficacy of a great propensity to rebleed over time. It is therefore cyanoacrylate injections (tissue glue) in achieving he- reasonable to decompress the portal vein with a TIPS as mostasis in bleeding fundic varices.134,135 Cyanoacry- the definitive procedure of choice in most patients before late glue leads to more rapid variceal obliteration and discharge from the hospital.144,145 It is often necessary to more effective hemostasis than alcohol injection.134 embolize prominent portosystemic collaterals at the time Severe complications associated with intravariceal cya- of TIPS to reduce the risk of bleeding. When this is not noacrylate glue injection include mediastinitis, CVA, done, nonselective b-blockers may be used to reduce the INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL 251 risks of rebleeding, although the data to support such an variceal hemorrhage; however, its use is limited due to approach are weak at best. In those with well-preserved systemic effects such as coronary and mesenteric ische- liver function, a surgical shunt can also provide long- mia.156 If vasopressin is used in conjunction with nitro- term relief from bleeding.146 glycerin, these effects can be minimized.157,158 Terlipressin is a synthetic analogue of vasopressin with a longer half-life and fewer side effects. It is Portal Hypertensive Gastropathy effective in the treatment of acute variceal bleeding Portal hypertensive gastropathy (PHG) is a manifes- with or without endoscopic therapy and has been shown tation of portal hypertension. Endoscopically it is to reduce mortality.125,159 It appears to be as effective as characterized by a mosaic mucosal pattern with varying vasopressin or endoscopic treatment126,160 in controlling degrees of submucosal hemorrhage. It is often asymp- acute variceal hemorrhage, but is not yet available in the tomatic but may lead to chronic transfusion–requiring United States. blood loss or acute bleeding (rarely). Although portal gastropathy is more often seen in the setting of gastro- esophageal varices, its severity does not correlate with Endoscopic Therapy portal pressure. Nevertheless, bleeding is often amelio- Endoscopic variceal band ligation (EBL) is currently the rated by reduction of portal pressure. Both octreotide preferred endoscopic technique for the management of and nonselective b-blockade can be helpful in decreas- esophageal varices. It is at least as effective as endoscopic ing acute bleeding and the degree of rebleeding from sclerotherapy (EST) but has a superior safety profile and PHG via reduction of portal blood flow.147–149 In lower complication rate.133,161,162 EBL also decreases refractory cases, TIPS can be effective at reducing the incidence of bleeding, when given as primary pro- transfusion requirements.150 phylaxis,163,164 and death165 from variceal bleeding. Band ligation leads to strangulation and subsequent obliteration of the banded varix. THERAPIES TO ACHIEVE HEMOSTASIS EST involves the injection of a sclerosant (sodium morrhuate, ethanolamine, or polidocanol) into or around Drug Therapy a varix. This leads to coagulative necrosis and obliter- Drug therapy is an integral component of the manage- ation of varices in the vicinity of the injection. Compli- ment of acute portal hypertensive hemorrhage and cations related to EST tend to occur more frequently and should be started on presentation. To optimize the be more severe than with EBL and include esophageal effectiveness of drug or endoscopic therapy, clotting ulceration, stricturing, esophageal perforation, pleural abnormalities must be corrected. Target INR and effusion, and sepsis. Despite a higher complication platelet count should be 1.5 and 75, respectively. In rate, a role still exists for EST. It can be a useful adjunct the setting of renal failure platelets may be dysfunc- to EBL in the setting of massive hemorrhage with poor tional and DDAVP (Desamino-D-Arginine Vasopres- visibility because the location of injection need not be as sin) should be considered. FFP alone or in combination precise to achieve hemostasis. with rFVIIa can be given to rapidly correct coagulop- Regardless of the choice of endoscopic manage- athy. A recent randomized, clinical trial showed that ment for acute bleeding, follow-up endoscopy within whengiveninadditiontostandardtherapy,100mg/kg 1 to 2 weeks for further banding is essential to decrease of rFVIIa may improve control of bleeding in patients the risk of rebleeding. EBL should then be continued in with advanced cirrhosis.151 the future until variceal obliteration is achieved. Somatostatin or octreotide, its synthetic analogue, stops acute bleeding from varices in 80% of cases.152 It does so through a reduction of portal pressure via effects Balloon Occlusion on vasoactive peptides or through the prevention of Balloon tamponade is effective in the 5 to 10% of postprandial hyperemia (blood meal). Octreotide has patients in which hemostasis cannot be achieved acutely an excellent safety profile and can be given initially as a with medical or endoscopic therapy. It successfully stops subcutaneous bolus of 50 to 100 mg followed by a bleeding from esophagogastric varices through external continuous infusion of 50 mg/h for 3 to 5 days. Although compression of varices, but rebleeding occurs in 50%.166 it does decrease portal pressure acutely, these effects Many types of tubes exist (Sengsten-Blake Tube, Warne appear to be short lived due to rapid tachyphylaxis.153 Surgical Products, Ltd., Armagh, Ireland, UK; and Nevertheless, studies have shown a significant decrease Linton Tube, Bard Manufacturing, Covington, Geor- in rebleeding after endoscopic therapy in those receiving gia, USA) with mild variations; however, in most cases; octreotide infusion.154,155 inflation of the gastric balloon is adequate to stop Vasopressin reduces splanchnic blood flow in variceal hemorrhage. It is quite effective as a bridge to addition to portal pressure. It is effective in controlling more definitive therapy (TIPS or surgery) and cannot be 252 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

in place for more than 24 hours given the significant risk dures (Suguira or modification) or liver transplantation. of esophageal necrosis and rupture.167 If surgery is necessary, it is best done at a center with extensive experience.

Transjugular Intrahepatic Portosystemic Shunt (TIPS) COMPLICATIONS ASSOCIATED WITH TIPS involves placing a stent within the liver that VARICEAL BLEEDING bridges a branch of the intrahepatic hepatic vein with an intrahepatic branch of the portal vein, allowing Hepatic Encephalopathy diversion of blood flow away from the cirrhotic liver, The initial approach to the patient with HE should focus decompressing portal pressures, and reducing the im- on the identification and correction of any precipitant in petus to bleed. In experienced hands TIPS is a very addition to treatment of the encephalopathy. Common effective method for stopping acute hemorrhage from precipitants include gastrointestinal (GI) bleeding, esophageal varices but can be less effective in gastric medications, infection, dehydration, electrolyte distur- variceal bleeding.168 In the setting of variceal bleeding, bances, constipation, excessive protein load, portosyste- TIPS should be reserved for cases that are refractory to mic shunting (TIPS or spontaneous), and worsening endoscopic therapy,169 orinthecaseofgastricvarices, liver function (Table 5). Potential precipitants such as used in conjunction with embolization. If recurrent these must be individually considered and subsequently bleeding occurs in a patient with a TIPS in place, the excluded. In the case of infection, spontaneous bacterial most important intervention is interrogation of the peritonitis (SBP) is the most common infection in this TIPS to document and treat thrombosis or stenosis. population and must be ruled out with a diagnostic Until recently, TIPS was complicated by fre- paracentesis as already discussed. Often, HE is the quent stenosis and thrombosis.168 Polytetrafluoroethy- only manifestation of SBP. lene (PTFE)-coated stents have significantly improved stent patency and the need for reintervention.170–172 TREATMENT OF HEPATIC ENCEPHALOPATHY Although they have not been directly compared with Nonabsorbable disaccharides and antibiotics have been surgical shunts, these data suggest they offer comparable shown to modify gut flora and decrease blood ammonia results. levels, but these are not necessarily related (indicating nonbacterial sources of ammonia, which may also be decreased by these compounds). Lactulose is the first- Surgery line therapy for HE. It is most effective if given orally TIPS has significantly reduced the need for shunt and titrated to a dose that achieves three to four soft surgery; however, surgery remains a good option in bowel movements a day. A common mistake in the ICU selected cases when TIPS is not technically feasible or is continued lactulose despite diarrhea in the encepha- fails or in patients with significant portal hypertension in lopathic patient. Not only will this not improve ence- the face of preserved hepatic synthetic function. The phalopathy, it may worsen it through free water long-term patency rate of shunt surgery is thought to be depletion. If the patient is having adequate bowel move- superior to that of TIPS; however, newer coated stents ments on lactulose, but continues to be confused, several may challenge this assumption.170–172 Surgical alterna- agents can be added. Nonabsorbable antibiotics such as tives for acute portal hypertensive hemorrhage include neomycin or rifaxamin are effective for the treatment of total or selective shunt surgery, devascularization proce- HE either alone or in conjunction with lactulose. Met- ronidazole is also efficacious; however, side effects limit Table 5 Precipitants of Hepatic Encephalopathy prolonged use. Zinc is a cofactor for the urea cycle and can increase the clearance of ammonia. Zinc levels are Infection decreased in patients with cirrhosis and HE. Supple- Gastrointestinal bleeding mentation with zinc sulfate 600 mg/d normalizes zinc Medical noncompliance levels, decreases ammonia, and improves HE.173 Medication—sedatives, narcotics, other Branched-chain amino acids have not convincingly Electrolyte disturbances shown improvement in HE; however, they may be Portosystemic shunting considered in patients that are not receiving protein in Transjugular intrahepatic portosystemic shunt any form.174,175 Spontaneous When HE is refractory to medical treatment Dehydration other possibilities must be entertained. In those with a Excessive protein load TIPS, occlusion or narrowing of the stent lumen can Constipation improve mental status.176,177 If no TIPS or surgical Worsening liver function shunt is present, abdominal imaging should be obtained INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL 253

Table 6 Diagnostic Criteria for Hepatorenal Syndrome location from the gut is thought to be the most common (International Ascites Club) mode of ascitic fluid inoculation.189,190 Predisposing MAJOR factors for the development of SBP include advanced Chronic or acute liver disease with advanced hepatic failure liver disease, gastrointestinal bleeding, ascitic total pro- and portal hypetension tein fluid content 1 g/dL and a previous history of 181,191–193 Creatinine> 1.5mg/dLor24-hourcreatinineclearance< 40mL/min SBP. Absence of shock, ongoing infection, use of nephrotoxic drugs, gastrointestinal or renal fluid losses > 500 g/d or INTERPRETATION OF A DIAGNOSTIC PERITONEAL TAP > 1000 g/d in the setting of edema It is crucial to have a very low threshold to perform a Urine protein < 500 mg/dL diagnostic paracentesis in the patient with suspected No ultrasonographic evidence of primary renal disease SBP. Ideally, this should be done prior to the initia- No sustained improvement in renal function after hydration tion of antibiotics. Peritoneal fluid should be sent MINOR for cell count, culture, albumin, total protein, LDH Urine sodium < 10 mEq/L (lactate dehydrogenase) and glucose. Blood culture Urine osmolality > plasma osmolality bottles should be inoculated at the bedside to improve Urine red blood cells < 50 per high power field yield. Urine output < 500 mL/d SBP is defined as an ascitic fluid polymorphonu- 3 Serum sodium < 130 mEq/L clear (PMN) 250 cells/mm , in the setting of a positive monomicrobial ascitic fluid culture.194,195 Cul- For the diagnosis of hepatorenal syndrome, all major criteria must be met. Minor criteria are supportive but not necessary for the diagnosis. ture positivity can fluctuate from one tap to the next; thus culture-negative neutrocytic ascites should be to look for a prominent portosystemic collateral that treated with antibiotics as previously outlined.196 could be radiographically embolized.178 Monomicrobial non-neutrocytic bacterascites is another common variant of SBP. It is defined as a fluid cell count < 250 cells/ mm3 with a positive culture.197 Infection Runyon and Hoefs and Chu et al found that 62 to 86% Bacterial infections complicate 35 to 66% of cases of of cases of monomicrobial bacterial ascites resolve spon- gastrointestinal bleeding in patients with AoCLF.179–184 taneously, and those that did not resolve were sympto- Not only is infection common after bleeding, it may also matic on presentation.197,198 Thus, in a clinically stable provoke rebleeding.179 Furthermore, bacterial infection asymptomatic patient, one could observe or consider and the use of prophylactic antibiotics are independently repeat diagnostic paracentesis. However, in a critically associated with failure to control variceal hemorrhage in ill patient with AoCLF in the ICU, antibiotic therapy the first 5 days of admission.180 Many randomized, may be the best course of action. controlled trials have shown that antibiotic prophylaxis targeted at enteric organisms (such as quinolones or TREATMENT OF SPONTANEOUS BACTERIAL PERITONITIS third-generation cephalosporin) is effective in the pre- Patients should be given a non-nephrotoxic antibiotic vention of postbleeding infection in cirrhotic patients. In with good enteric coverage such as a third-generation addition, a meta-analysis of randomized, controlled cephalosporin. Cefotaxime 2 g (q8h) is the best- trials concluded that antibiotic prophylaxis resulted in studied antibiotic for the treatment of SBP.199,200 less infections and improved short-term survival in Other antibiotics of comparable spectrum can be bleeding patients with cirrhosis.185 Given these data, used and can be tailored if the organism is identified. prophylactic systemic antibiotics should be given to Once the patient has been on antibiotics for 48 hours, cirrhotic patients with gastrointestinal hemorrhage. a diagnostic tap must be repeated to assess response to treatment. If there is not a significant decrement in the white blood cell (WBC) count, antibiotic coverage Spontaneous Bacterial Peritonitis should be broadened. Once treatment efficacy is estab- SBP is a frequent and severe complication in those with lished, antibiotics should be given for 5 days.201 Intra- cirrhosis and ascites.186 It is associated with significant venous albumin is integral to the treatment of SBP morbidity and mortality by precipitating renal failure in andshouldbeusedinconjunctionwithantibiotics.It 30%,187 worsening HE, and causing hemodynamic col- has been shown in a randomized, controlled trial to lapse in an already critically ill patient. The deterioration decrease the incidence of renal failure and subsequent of renal function is the most sensitive predictor of in- mortality when compared with antibiotics alone.202 hospital mortality.187,188 Renal failure often results from Based on these data, albumin should be given at a a reduction in effective circulating blood volume, cyto- dose of 1.5 mg/kg on day 1 and 1 mg/kg on day 3. A kine surges, and activation of the renin-angiotensin recent study compared albumin to plasma expansion system precipitated by infection.187,188 Bacterial trans- with hydroxyethyl starch. Fernandez and colleagues 254 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

found that only albumin improved hemodynamics in Table 6 illustrates the International Ascites Club classi- patients with SBP, suggesting that it may also have fication of HRS. direct effects on the vascular endothelium.203 Lifelong The pathophysiology of HRS is complex. secondary antibiotic prophylaxis is mandatory in the Splanchnic arteriolar vasodilation leads to central vaso- patient with a history of SBP. Oral quinolones are dilation and compensatory activation of systemic and most commonly used (norfloxacin); however, many renal vasoconstrictor systems.107,211 The resultant renal antibiotics are effective for secondary prophylaxis of vasoconstriction leads to reduced glomerular filtration SBP. rate and increased water and sodium retention.

ASCITES Treatment of Hepatorenal Syndrome Ascitesistheresultofavidwaterandsodiumretention Liver transplantation is the ultimate treatment for characteristic of the altered hemodynamics of cirrhosis HRS. After transplantation renal function returns to and portal hypertension. It is associated with a 50% baseline in most cases.212,213 Combination drug ther- 2-year survival. Uncomplicated ascites is managed apy that counteracts renal and systemic vasoconstriction with sodium restriction (< 88 mmol/d) and diuretics; leading to arterial hypotension and central hypovolemia potassium sparing (i.e., spironolactone) alone, or in with vasoconstrictors and plasma expanders, respec- combination with a loop diuretic (i.e., furosemide). tively, is the most effective strategy. Terlipressin, a Diuretics are advanced until therapeutic efficacy is long-acting vasopressin analogue that stimulates achieved or limited by worsening renal function or splanchnic V1a vasopressin receptors increases blood hyponatremia. In diuretic-refractory or resistant cases pressure, GFR (glomerular filtration rate), and urine repeat large-volume paracentesis (LVP) with albumin volume in patients with HRS.214,215 Unfortunately, infusion, TIPS, or peritonovenous shunts can be terlipressin is not yet available in the United States. effective in improving the ascites but does not improve In a small study of patients with HRS I, the combina- survival.204,205 tion of the a-agonist midodrine (7.5 mg tid), octreotide Ascites can be a difficult problem to manage (100 g SQ tid), and albumin (25 g/day) was effective in in the ICU. Copious colloid and crystalloid infusion improving renal function.216 In a more recent study, inevitably worsens ascites and diuretic use is often these findings were confirmed and insertion of a TIPS limited by hyponatremia, hypotension, or renal failure. in a subset of patients led to further improvement in Massive ascites can also alter respiratory mechanics and renal function.217 make breathing more labored or mechanical ventilation more challenging. Occasionally, massive ascites can worsen renal failure through compression of the renal LIVER TRANSPLANTATION—CHRONIC arteries. LVP should be reserved for patient discomfort LIVER DISEASE and improvement of respiratory mechanics when possi- Allocation of organs in chronic liver disease changed on ble to avoid large-volume shifting and activation of February 27, 2002. The model of end-stage liver disease vasoactive neurohumoral systems after paracentesis that (MELD) system was adopted to objectify the way in can worsen renal perfusion. Such changes can be mini- which livers were allocated in the United States. It is a mized with the use of albumin (6 to 8 g/L removed). survival model based on a composite of three laboratory Albumin administration helps maintain intravascular values: serum bilirubin, serum creatinine, and INR. volume and minimize postparacentesis circulatory dys- The model was originally used to assess short-term function.205,206 mortality in cirrhotic patients undergoing elective TIPS placement.218 This model was subsequently va- lidated as an independent predictor of survival in RENAL FAILURE patients with cirrhosis.219,220 Thus priority on the liver Twenty percent of cirrhotic patients with tense ascites transplant waiting list is based on the patient’s blood develop renal failure characterized by the hepatorenal group and the MELD score without emphasis on syndrome (HRS).207,208 HRS is defined as functional waiting time. renal impairment in a patient with advanced liver disease in the setting of normal tubular function and renal histology209 (Table 6). Two types of HRS have been SUMMARY described; HRS I and HRS II, based upon the rapidity Management of the patient with acute or chronic and extent of renal failure.210 HRS I is characterized by a hepatic failure remains a challenging problem, despite rapid and severe deterioration of renal function with advances in intensive care. Liver failure typically has survival measured in days to weeks, and HRS II repre- profound effects on other organ systems and the effects sents a more indolent and stable renal dysfunction. of therapeutic interventions on other organs must be INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL 255 considered. A multidisciplinary approach is most effec- 19. Lee WM. Acetaminophen and the U.S. Acute Liver Failure tive and urgent transfer to a transplant center is man- Study Group: lowering the risks of hepatic failure. Hepatol- datory in potential transplant candidates. Ideally, good, ogy 2004;40:6–9 comprehensive intensive care can support the patient 20. Harrison PM, Keays R, Bray GP, Alexander GJ, Williams R. Improved outcome of paracetamol-induced fulminant hepa- into spontaneous hepatic recovery; however, often tic failure by late administration of acetylcysteine. Lancet the goal of therapy is to bridge patients to definitive 1990;335:1572–1573 therapy—liver transplantation. 21. Donaldson BW, Gopinath R, Wanless IR, et al. The role of transjugular liver biopsy in fulminant liver failure: relation to other prognostic indicators. Hepatology 1993;18:1370–1376 REFERENCES 22. Chung PY, Sitrin MD, Te HS. Serum phosphorus levels predict clinical outcome in fulminant hepatic failure. Liver 1. Trey C, Lipworth L, Davidson CS. Halothane and liver Transpl 2003;9:248–253 damage. N Engl J Med 1969;280:562–563 23. Schmidt LE, Dalhoff K. Alpha-fetoprotein is a predictor of 2. Trey C, Davidson CS. The management of fulminant outcome in acetaminophen-induced liver injury. Hepatology hepatic failure. Prog Liver Dis 1970;3:282–298 2005;41:26–31 3. Bernal W, Wendon J. Liver transplantation in adults with 24. Baquerizo A, Anselmo D, Shackleton C, et al. Phosphorus as acute liver failure. J Hepatol 2004;40:192–197 an early predictive factor in patients with acute liver failure. 4. Blei AT. Medical therapy of brain edema in fulminant Transplantation 2003;75:2007–2014 hepatic failure. Hepatology 2000;32:666–669 25. Shami VM, Caldwell SH, Hespenheide EE, Arseneau KO, 5. Mas A, Rodes J. Fulminant hepatic failure. Lancet 1997;349: Bickston SJ, Macik BG. Recombinant activated factor VII 1081–1085 for coagulopathy in fulminant hepatic failure compared with 6. Larsen FS, Wendon J. Brain edema in liver failure: basic conventional therapy. Liver Transpl 2003;9:138–143 physiologic principles and management. Liver Transpl 2002; 26. Bernal W. Intensive care support therapy. Liver Transpl 8:983–989 2003;9(suppl 9):S15–S17 7. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early 27. Vaquero J, Chung C, Cahill ME, Blei AT. Pathogenesis of indicators of prognosis in fulminant hepatic failure. Gastro- hepatic encephalopathy in acute liver failure. Semin Liver enterology 1989;97:439–446 Dis 2003;23:259–269 8. Izumi S, Langley PG, Wendon J, et al. Coagulation factor V 28. Vaquero J, Blei AT. Etiology and management of fulminant levels as a prognostic indicator in fulminant hepatic failure. hepatic failure. Curr Gastroenterol Rep 2003;5:39–47 Hepatology 1996;23:1507–1511 29. Wijdicks EF, Nyberg SL. Propofol to control intracranial 9. Pereira LM, Langley PG, Hayllar KM, Tredger JM, pressure in fulminant hepatic failure. Transplant Proc 2002; Williams R. Coagulation factor V and VIII/V ratio as 34:1220–1222 predictors of outcome in paracetamol induced fulminant 30. Steinberg KP. Stress-related mucosal disease in the critically hepatic failure: relation to other prognostic indicators. Gut ill patient: risk factors and strategies to prevent stress-related 1992;33:98–102 bleeding in the intensive care unit. Crit Care Med 2002; 10. Lee WM. Acute liver failure in the United States. Semin 30(Suppl 6):S362–S364 Liver Dis 2003;23:217–226 31. Jalan R. Intracranial hypertension in acute liver failure: 11. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin pathophysiological basis of rational management. Semin SB. Acetaminophen hepatotoxicity in alcoholics: a therapeutic Liver Dis 2003;23:271–282 misadventure. Ann Intern Med 1986;104:399–404 32. Ellis A, Wendon J. Circulatory, respiratory, cerebral, and 12. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a renal derangements in acute liver failure: pathophysiology prospective study of acute liver failure at 17 tertiary care cen- and management. Semin Liver Dis 1996;16:379–388 ters in the United States. Ann Intern Med 2002;137:947– 33. Trewby PN, Williams R. Pathophysiology of hypotension in 954 patients with fulminant hepatic failure. Gut 1977;18:1021– 13. Makin AJ, Wendon J, Williams R. A 7-year experience of 1026 severe acetaminophen-induced hepatotoxicity (1987–1993). 34. Rolando N, Wade J, Davalos M, Wendon J, Philpott- Gastroenterology 1995;109:1907–1916 Howard J, Williams R. The systemic inflammatory response 14. Zimmerman HJ, Maddrey WC. Acetaminophen (paraceta- syndrome in acute liver failure. Hepatology 2000;32(4 Pt 1): mol) hepatotoxicity with regular intake of alcohol: analysis of 734–739 instances of therapeutic misadventure. Hepatology 1995;22: 35. Bouachour G, Tirot P, Varache N, Gouello JP, Harry P, 767–773 Alquier P. Hemodynamic changes in acute adrenal insuffi- 15. Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetami- ciency. Intensive Care Med 1994;20:138–141 nophen toxicity in an urban county hospital. N Engl J Med 36. Bollaert PE, Charpentier C, Levy B, Debouverie M, 1997;337:1112–1117 Audibert G, Larcan A. Reversal of late septic shock with 16. McClain CJ, Kromhout JP, Peterson FJ, Holtzman JL. supraphysiologic doses of hydrocortisone. Crit Care Med Potentiation of acetaminophen hepatotoxicity by alcohol. 1998;26:645–650 JAMA 1980;244:251–253 37. McCashland TM, Shaw BW Jr, Tape E. The American 17. Murphy R, Swartz R, Watkins PB. Severe acetaminophen experience with transplantation for acute liver failure. Semin toxicity in a patient receiving isoniazid. Ann Intern Med Liver Dis 1996;16:427–433 1990;113:799–800 38. Davies MH, Mutimer D, Lowes J, Elias E, Neuberger J. 18. Prescott LF, Critchley JA. The treatment of acetaminophen Recovery despite impaired cerebral perfusion in fulminant poisoning. Annu Rev Pharmacol Toxicol 1983;23:87–101 hepatic failure. Lancet 1994;343:1329–1330 256 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

39. Wyke RJ, Yousif-Kadaru AG, Rajkovic IA, Eddleston AL, 57. Davenport A, Will EJ, Davison AM. Continuous vs. Williams R. Serum stimulatory activity and polymorpho- intermittent forms of haemofiltration and/or dialysis in the nuclear leucocyte movement in patients with fulminant management of acute renal failure in patients with defective hepatic failure. Clin Exp Immunol 1982;50:442–449 cerebral autoregulation at risk of cerebral oedema. Contrib 40. Wyke RJ, Rajkovic IA, Eddleston AL, Williams R. Nephrol 1991;93:225–233 Defective opsonisation and complement deficiency in serum 58. O’Grady JG. Paracetamol hepatotoxicity: how to prevent. from patients with fulminant hepatic failure. Gut 1980;21: J R Soc Med 1997;90:368–370 643–649 59. Blei AT. Hypothermia for hypertension. Lancet 1999; 41. Altin M, Hughes RD, Williams R. Neutrophil adherence (9195):2082 during hemoperfusion in fulminant hepatic failure. Int J 60. Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Artif Organs 1982;5:315–317 Cerebral herniation in patients with acute liver failure is 42. Clapperton M, Rolando N, Sandoval L, Davies E, Williams correlated with arterial ammonia concentration. Hepatology R. Neutrophil superoxide and hydrogen peroxide production 1999;29:648–653 in patients with acute liver failure. Eur J Clin Invest 1997; 61. Strauss GI, Knudsen GM, Kondrup J, Moller K, Larsen FS. 27:164–168 Cerebral metabolism of ammonia and amino acids in patients 43. Rolando N, Harvey F, Brahm J, et al. Prospective study of with fulminant hepatic failure. Gastroenterology 2001;121: bacterial infection in acute liver failure: an analysis of fifty 1109–1119 patients. Hepatology 1990;11:49–53 62. Strauss GI, Christiansen M, Moller K, Clemmesen JO, 44. Rolando N, Philpott-Howard J, Williams R. Bacterial and Larsen FS, Knudsen GM. S-100b and neuron-specific fungal infection in acute liver failure. Semin Liver Dis 1996; enolase in patients with fulminant hepatic failure. Liver 16:389–402 Transpl 2001;7:964–970 45. Wade J, Rolando N, Philpott-Howard J, Wendon J. Timing 63. Keays RT, Alexander GJ, Williams R. The safety and value and aetiology of bacterial infections in a liver intensive care of extradural intracranial pressure monitors in fulminant unit. J Hosp Infect 2003;53:144–146 hepatic failure. J Hepatol 1993;18:205–209 46. Rolando N, Gimson A, Wade J, Philpott-Howard J, 64. Lidofsky SD, Bass NM, Prager MC, et al. Intracranial Casewell M, Williams R. Prospective controlled trial of pressure monitoring and liver transplantation for fulminant selective parenteral and enteral antimicrobial regimen in hepatic failure. Hepatology 1992;16:1–7 fulminant liver failure. Hepatology 1993;17:196–201 65. Donovan JP, Shaw BW Jr, Langnas AN, Sorrell MF. Brain 47. Salmeron JM, Tito L, Rimola A, et al. Selective intestinal water and acute liver failure: the emerging role of intracranial decontamination in the prevention of bacterial infection in pressure monitoring. Hepatology 1992;16:267–268 patients with acute liver failure. J Hepatol 1992;14:280–285 66. Larsen FS, Knudsen GM, Hansen BA. Pathophysiological 48. Rolando N, Wade JJ, Stangou A, et al. Prospective study changes in cerebral circulation, oxidative metabolism and comparing the efficacy of prophylactic parenteral antimicro- blood-brain barrier in patients with acute liver failure: tailored bials, with or without enteral decontamination, in patients cerebral oxygen utilization. J Hepatol 1997;27: 231–238 with acute liver failure. Liver Transpl Surg 1996;2:8–13 67. Toftengi F, Larsen FS. Management of patients with 49. Vaquero J, Polson J, Chung C, et al. Infection and the fulminant hepatic failure and brain edema. Metab Brain progression of hepatic encephalopathy in acute liver failure. Dis 2004;19:207–214 Gastroenterology 2003;125:755–764 68. Blei AT, Olafsson S, Webster S, Levy R. Complications of 50. Billiau A, Vandekerckhove F. Cytokines and their interac- intracranial pressure monitoring in fulminant hepatic failure. tions with other inflammatory mediators in the pathogenesis Lancet 1993;341:157–158 of sepsis and septic shock. Eur J Clin Invest 1991;21:559–573 69. Vaquero J, Blei A, Fontana RJ, et al. Complications and use 51. Jalan R, Pollok A, Shah SH, Madhavan K, Simpson KJ. of intracranial pressure monitoring in patients with acute Liver derived pro-inflammatory cytokines may be important liver failure and severe encephalopathy. Liver Transpl 2005; in producing intracranial hypertension in acute liver failure. J 12:1581–1589 Hepatol 2002;37:536–538 70. Cordoba J, Blei AT. Cerebral edema and intracranial 52. Bihari DJ, Gimson AE, Williams R. Cardiovascular, pressure monitoring. Liver Transpl Surg 1995;1:187–194 pulmonary and renal complications of fulminant hepatic 71. Caldwell SH, Chang C, Macik BG. Recombinant activated failure. Semin Liver Dis 1986;6:119–128 factor VII (rFVIIa) as a hemostatic agent in liver disease: 53. Briegel J, Forst H, Haller M, et al. Stress doses of a break from convention in need of controlled trials. hydrocortisone reverse hyperdynamic septic shock: a pro- Hepatology 2004;39:592–598 spective, randomized, double-blind, single-center study. Crit 72. Murphy N, Auzinger G, Bernel W, Wendon J. The effect of Care Med 1999;27:723–732 hypertonic sodium chloride on intracranial pressure in 54. Harry R, Auzinger G, Wendon J. The clinical importance of patients with acute liver failure. Hepatology 2004;39:464– adrenal insufficiency in acute hepatic dysfunction. Hepatol- 470 ogy 2002;36:395–402 73. Clemmesen JO, Kondrup J, Nielsen LB, Larsen FS, Ott P. 55. Davenport A, Will EJ, Davison AM, et al. Changes in Effects of high-volume plasmapheresis on ammonia, urea, intracranial pressure during haemofiltration in oliguric and amino acids in patients with acute liver failure. Am J patients with grade IV hepatic encephalopathy. Nephron Gastroenterol 2001;96:1217–1223 1989;53:142–146 74. Awad SS, Swaniker F, Magee J, Punch J, Bartlett RH. 56. Davenport A, Will EJ, Davidson AM. Improved cardiovas- Results of a phase I trial evaluating a liver support device cular stability during continuous modes of renal replacement utilizing albumin dialysis. Surgery 2001;130:354–362 therapy in critically ill patients with acute hepatic and renal 75. Rose C, Michalak A, Rao KV, Quack G, Kircheis G, failure. Crit Care Med 1993;21:328–338 Butterworth RF. L-ornithine-L-aspartate lowers plasma and INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL 257

cerebrospinal fluid ammonia and prevents brain edema in rats module inoculated with liver cells. Hepatology 1993;17:258– with acute liver failure. Hepatology 1999;30:636–640 265 76. Canalese J, Gimson AE, Davis C, Mellon PJ, Davis M, 92. Sussman NL, Kelly JH. Extracorporeal liver support: cell- Williams R. Controlled trial of dexamethasone and mannitol based therapy for the failing liver. Am J Kidney Dis for the cerebral oedema of fulminant hepatic failure. Gut 1997;30(5, Suppl 4):S66–S71 1982;23:625–629 93. Demetriou AA, Brown RS Jr, Busuttil RW, et al. Prospec- 77. Ede RJ, Gimson AE, Bihari D, Williams R. Controlled tive, randomized, multicenter, controlled trial of a bio- hyperventilation in the prevention of cerebral oedema in artificial liver in treating acute liver failure. Ann Surg fulminant hepatic failure. J Hepatol 1986;2:43–51 2004;239:660–667 discussion 667–670 78. Strauss GI, Moller K, Holm S, Sperling B, Knudsen GM, 94. Ellis AJ, Hughes RD, Wendon JA, et al. Pilot-controlled Larsen FS. Transcranial Doppler sonography and internal trial of the extracorporeal liver assist device in acute liver jugular bulb saturation during hyperventilation in patients failure. Hepatology 1996;24:1446–1451 with fulminant hepatic failure. Liver Transpl 2001;7:352– 95. Jalan R, Sen S, Williams R. Prospects for extracorporeal liver 358 support. Gut 2004;53:890–898 79. Strauss G, Hansen BA, Knudsen GM, Larsen FS. 96. Stange J, Mitzner S, Ramlow W, Gliesche T, Hickstein H, Hyperventilation restores cerebral blood flow autoregulation Schmidt R. A new procedure for the removal of protein in patients with acute liver failure. J Hepatol 1998;28:199– bound drugs and toxins. ASAIO J 1993;39:M621–M625 203 97. Stange J, Ramlow W, Mitzner S, Schmidt R, Klinkmann H. 80. Jensen K, Ohrstrom J, Cold GE, Astrup J. Indomethacin Dialysis against a recycled albumin solution enables the (Confortid) in severe head injury and elevated intracranial removal of albumin-bound toxins. Artif Organs 1993;17: pressure (ICP). Acta Neurochir Suppl (Wien) 1992;55:47– 809–813 48 98. Stange J, Mitzner SR, Klammt S, et al. Liver support by 81. Chung C, Gottstein J, Blei AT. Indomethacin prevents the extracorporeal blood purification: a clinical observation. development of experimental ammonia-induced brain edema Liver Transpl 2000;6:603–613 in rats after portacaval anastomosis. Hepatology 2001;34: 99. Lutkes P, Lutz J, Loock J, et al. Continuous venovenous 249–254 hemodialysis treatment in critically ill patients after 82. Tofteng F, Larsen FS. The effect of indomethacin on liver transplantation. Kidney Int Suppl 1999;(72):S71–S74 intracranial pressure, cerebral perfusion and extracellular 100. Mitzner SR, Stange J, Klammt S, et al. Improvement of lactate and glutamate concentrations in patients with hepatorenal syndrome with extracorporeal albumin dialysis fulminant hepatic failure. J Cereb Blood Flow Metab 2004; MARS: results of a prospective, randomized, controlled 24:798–804 clinical trial. Liver Transpl 2000;6:277–286 83. Forbes A, Alexander GJ, O’Grady JG, et al. Thiopental 101. Khuroo MS, Farahat KL. Molecular adsorbent recirculating infusion in the treatment of intracranial hypertension system for acute and acute-on-chronic liver failure: a meta- complicating fulminant hepatic failure. Hepatology 1989; analysis. Liver Transpl 2004;10:1099–1106 10:306–310 102. Sen SSC, Williams R. Artificial liver support: overview of 84. Peignoux M, Bernuau J, Benhamou JP. Total hepatectomy registry and controlled trials. In: Arroyo VFX, Garcia-Pagan and hepatic vascular exclusion in the rat: a comparison, with JC, eds. Progress in the Treatment of Liver Diseases. special reference to the influence of body temperature. Clin Barcelona: Ars Medica; 2003:429–435 Sci (Lond) 1982;62:273–277 103. Singh N, Gayowski T, Wagener MM, Marino IR. Outcome 85. Eguchi S, Kamlot A, Ljubimova J, et al. Fulminant hepatic of patients with cirrhosis requiring intensive care unit failure in rats: survival and effect on blood chemistry and liver support: prospective assessment of predictors of mortality. regeneration. Hepatology 1996;24:1452–1459 J Gastroenterol 1998;33:73–79 86. Jalan R, Damink SW, Deutz NE, Lee A, Hayes PC. 104. Kress JP, Rubin A, Pohlman AS, Hall JB. Outcomes of Moderate hypothermia for uncontrolled intracranial hyper- critically ill patients denied consideration for liver transplan- tension in acute liver failure. Lancet 1999;354:1164–1168 tation. Am J Respir Crit Care Med 2000;162(2 Pt 1):418– 87. Jalan R, Olde Damink SW, Deutz NE, et al. Moderate 423 hypothermia prevents cerebral hyperemia and increase in 105. Zimmerman JE, Wagner DP, Seneff MG, Becker RB, Sun intracranial pressure in patients undergoing liver transplan- X, Knaus WA. Intensive care unit admissions with cirrhosis: tation for acute liver failure. Transplantation 2003;75:2034– risk-stratifying patient groups and predicting individual 2039 survival. Hepatology 1996;23:1393–1401 88. Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. 106. Aggarwal A, Ong JP, Younossi ZM, Nelson DR, Hoffman- Moderate hypothermia in patients with acute liver failure Hogg L, Arroliga AC. Predictors of mortality and resource and uncontrolled intracranial hypertension. Gastroenterol- utilization in cirrhotic patients admitted to the medical ICU. ogy 2004;127:1338–1346 Chest 2001;119:1489–1497 89. Bernuau J. Acute liver failure: avoidance of deleterious 107. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen cofactors and early specific medical therapy for the liver are JH, Rodes J. Peripheral arterial vasodilation hypothesis: a better than late intensive care for the brain. J Hepatol proposal for the initiation of renal sodium and water 2004;41:152–155 retention in cirrhosis. Hepatology 1988;8:1151–1157 90. Munoz SJ. Hypothermia may impair hepatic regeneration 108. Gores GJ, Wiesner RH, Dickson ER, Zinsmeister AR, in acute liver failure. Gastroenterology 2005;128:1143–1144 Jorgensen RA, Langworthy A. Prospective evaluation of author reply 1144–1145 esophageal varices in primary biliary cirrhosis: development, 91. Rozga J, Williams F, Ro MS, et al. Development of a natural history, and influence on survival. Gastroenterology bioartificial liver: properties and function of a hollow-fiber 1989;96:1552–1559 258 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

109. Groszmann RJ, Bosch J, Grace ND, et al. Hemodynamic 127. Watanabe K, Kimura K, Matsutani S, Ohto M, Okuda K. events in a prospective randomized trial of propranolol versus Portal hemodynamics in patients with gastric varices: a study in placebo in the prevention of a first variceal hemorrhage. 230 patients with esophageal and/or gastric varices using portal Gastroenterology 1990;99:1401–1407 vein catheterization. Gastroenterology 1988;95:434–440 110. The North Italian Endoscopic Club for the Study and 128. Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Treatment of Esophageal Varices. Prediction of the first Prevalence, classification and natural history of gastric variceal hemorrhage in patients with cirrhosis of the liver and varices: a long-term follow-up study in 568 portal hyperten- esophageal varices: a prospective multicenter study. N Engl J sion patients. Hepatology 1992;16:1343–1349 Med 1988;319:983–989 129. Kim T, Shijo H, Kokawa H, et al. Risk factors for hem- 111. Mahl TC, Groszmann RJ. Pathophysiology of portal orrhage from gastric fundal varices. Hepatology 1997;25:307– hypertension and variceal bleeding. Surg Clin North Am 312 1990;70:251–266 130. Ohnishi K, Sato S, Saito M, et al. Clinical and portal 112. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, hemodynamic features in cirrhotic patients having a large Atterbury CE, Glickman M. Portal pressure, presence of spontaneous splenorenal and/or gastrorenal shunt. Am J gastroesophageal varices and variceal bleeding. Hepatology Gastroenterol 1986;81:450–455 1985;5:419–424 131. Rinella ME, Shah D, Vogelzang RL, Blei AT, Flamm SL. 113. Vorobioff J, Groszmann RJ, Picabea E, et al. Prognostic Fundal variceal bleeding after correction of portal hyperten- value of hepatic venous pressure gradient measurements in sion in patients with cirrhosis. Gastrointest Endosc 2003;58: alcoholic cirrhosis: a 10-year prospective study. Gastroenter- 122–127 ology 1996;111:701–709 132. Thakeb F, Salem SA, Abdallah M, el Batanouny M. 114. Moitinho E, Escorsell A, Bandi JC, et al. Prognostic value of Endoscopic diagnosis of gastric varices. Endoscopy 1994; early measurements of portal pressure in acute variceal 26:287–291 bleeding. Gastroenterology 1999;117:626–631 133. Sarin SK, Govil A, Jain AK, et al. Prospective randomized 115. Grace ND, Groszmann RJ, Garcia-Tsao G, et al. Portal trial of endoscopic sclerotherapy versus variceal band ligation hypertension and variceal bleeding: an AASLD single topic for esophageal varices: influence on gastropathy, gastric symposium. Hepatology 1998;28:868–880 varices and variceal recurrence. J Hepatol 1997;26:826–832 116. Rossle M. Prevention of rebleeding from oesophageal-gastric 134. Sarin SK, Jain AK, Jain M, Gupta R. A randomized varices. Eur J Gastroenterol Hepatol 2001;13:343–348 controlled trial of cyanoacrylate versus alcohol injection in 117. Escorsell A, Bordas JM, Castaneda B, et al. Predictive value patients with isolated fundic varices. Am J Gastroenterol of the variceal pressure response to continued pharmacolo- 2002;97:1010–1015 gical therapy in patients with cirrhosis and portal hyperten- 135. Lo GH, Lai KH, Cheng JS, Chen MH, Chiang HT. A sion. Hepatology 2000;31:1061–1067 prospective, randomized trial of butyl cyanoacrylate injection 118. Chalasani N, Kahi C, Francois F, et al. Improved patient versus band ligation in the management of bleeding gastric survival after acute variceal bleeding: a multicenter, cohort varices. Hepatology 2001;33:1060–1064 study. Am J Gastroenterol 2003;98:653–659 136. Gallet B, Zemour G, Saudemont JP, Renard P, Hillion ML, 119. Benoit JN, Womack WA, Korthuis RJ, Wilborn WH, Hiltgen M. Echocardiographic demonstration of intracar- Granger DN. Chronic portal hypertension: effects on diac glue after endoscopic obturation of gastroesophageal gastrointestinal blood flow distribution. Am J Physiol 1986; varices. J Am Soc Echocardiogr 1995;8(5 Pt 1):759–761 250(4 Pt 1):G535–G539 137. Rickman OB, Utz JP, Aughenbaugh GL, Gostout CJ. 120. Graham DY, Smith JL. The course of patients after variceal Pulmonary embolization of 2-octyl cyanoacrylate after hemorrhage. Gastroenterology 1981;80:800–809 endoscopic injection therapy for gastric variceal bleeding. 121. Kravetz D, Bosch J, Arderiu M, Pilar Pizcueta M, Rodes J. Mayo Clin Proc 2004;79:1455–1458 Hemodynamic effects of blood volume restitution following 138. See A, Florent C, Lamy P, Levy VG, Bouvry M. Cerebro- a hemorrhage in rats with portal hypertension due to vascular accidents after endoscopic obturation of esophageal cirrhosis of the liver: influence of the extent of portal- varices with isobutyl-2-cyanoacrylate in 2 patients. Gastro- systemic shunting. Hepatology 1989;9:808–814 enterol Clin Biol 1986;10:604–607 122. Kruskall MS, Mintz PD, Bergin JJ, et al. Transfusion 139. Yang WL, Tripathi D, Therapondos G, Todd A, Hayes PC. therapy in emergency medicine. Ann Emerg Med 1988;17: Endoscopic use of human thrombin in bleeding gastric 327–335 varices. Am J Gastroenterol 2002;97:1381–1385 123. D’Amico G, De Franchis R. Upper digestive bleeding in 140. Yoshida T, Harada T, Shigemitsu T, Takeo Y, Miyazaki S, cirrhosis: posttherapeutic outcome and prognostic indicators. Okita K. Endoscopic management of gastric varices using a Hepatology 2003;38:599–612 detachable snare and simultaneous endoscopic sclerotherapy 124. El-Serag HB, Everhart JE. Improved survival after variceal and O-ring ligation. J Gastroenterol Hepatol 1999;14:730– hemorrhage over an 11-year period in the Department 735 of Veterans Affairs. Am J Gastroenterol 2000;95:3566– 141. Yoshida T, Hayashi N, Suzumi N, et al. Endoscopic ligation 3573 of gastric varices using a detachable snare. Endoscopy 125. Ioannou GN, Doust J, Rockey DC. Systematic review: 1994;26:502–505 terlipressin in acute oesophageal variceal haemorrhage. 142. Kanagawa H, Mima S, Kouyama H, Gotoh K, Uchida T, Aliment Pharmacol Ther 2003;17:53–64 Okuda K. Treatment of gastric fundal varices by balloon- 126. Escorsell A, Ruiz del Arbol L, Planas R, et al. Multicenter occluded retrograde transvenous obliteration. J Gastroenterol randomized controlled trial of terlipressin versus sclerother- Hepatol 1996;11:51–58 apy in the treatment of acute variceal bleeding: the TEST 143. Fukuda T, Hirota S, Sugimura K. Long-term results of study. Hepatology 2000;32:471–476 balloon-occluded retrograde transvenous obliteration for the INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL 259

treatment of gastric varices and hepatic encephalopathy. hemostatic balloon in patients with cirrhosis: a randomized J Vasc Interv Radiol 2001;12:327–336 controlled trial. Arch Med Res 1997;28:241–245 144. Sanyal AJ. The use and misuse of transjugular intrahepatic 161. Laine L, Cook D. Endoscopic ligation compared with portasystemic shunts. Curr Gastroenterol Rep 2000;2:61–71 sclerotherapy for treatment of esophageal variceal bleeding: 145. Chau TN, Patch D, Chan YW, Nagral A, Dick R, a meta-analysis. Ann Intern Med 1995;123:280–287 Burroughs AK. ‘‘Salvage’’ transjugular intrahepatic portosys- 162. Stiegmann GV, Goff JS, Michaletz-Onody PA, et al. temic shunts: gastric fundal compared with esophageal Endoscopic sclerotherapy as compared with endoscopic variceal bleeding. Gastroenterology 1998;114:981–987 ligation for bleeding esophageal varices. N Engl J Med 146. Henderson JM. Role of distal splenorenal shunt for long- 1992;326:1527–1532 term management of variceal bleeding. World J Surg 1994; 163. Sarin SK, Lamba GS, Kumar M, Misra A, Murthy NS. 18:205–210 Comparison of endoscopic ligation and propranolol for the 147. Merli M, Salerno F, Riggio O, et al. Transjugular intrahepatic primary prevention of variceal bleeding. N Engl J Med portosystemic shunt versus endoscopic sclerotherapy for the 1999;340:988–993 prevention of variceal bleeding in cirrhosis: a randomized 164. Sarin SK, Guptan RK, Jain AK, Sundaram KR. A multicenter trial. Gruppo Italiano Studio Trends Pharmacol randomized controlled trial of endoscopic variceal band Sci (G.I.S.T.). Hepatology 1998;27:48–53 ligation for primary prophylaxis of variceal bleeding. Eur J 148. Zhou JH, Liu CY, Zhang RH, Wang HR, Liu KJ. Effects of Gastroenterol Hepatol 1996;8:337–342 octreotide on gallbladder pressure and myoelectric activity of 165. Lay CS, Tsai YT, Teg CY, et al. Endoscopic variceal ligation Oddi sphincter in rabbits. World J Gastroenterol 1998;4: in prophylaxis of first variceal bleeding in cirrhotic patients 238–241 with high-risk esophageal varices. Hepatology 1997;25: 149. Garcia N, Sanyal AJ. Portal hypertensive gastropathy and 1346–1350 gastric antral vascular ectasia. Curr Treat Options Gastro- 166. Harry R, Wendon J. Management of variceal bleeding. Curr enterol 2001;4:163–171 Opin Crit Care 2002;8:164–170 150. Kamath PS, Lacerda M, Ahlquist DA, McKusick MA, 167. Chojkier M, Conn HO. Esophageal tamponade in the Andrews JC, Nagorney DA. Gastric mucosal responses to treatment of bleeding varices: a decadel progress report. Dig intrahepatic portosystemic shunting in patients with cirrho- Dis Sci 1980;25:267–272 sis. Gastroenterology 2000;118:905–911 168. Sanyal AJ, Freedman AM, Luketic VA, et al. The natural 151. Bosch J, Thabut D, Bendtsen F, et al. Recombinant factor history of portal hypertension after transjugular intrahepa- VIIa for upper gastrointestinal bleeding in patients with tic portosystemic shunts. Gastroenterology 1997;112:889– cirrhosis: a randomized, double-blind trial. Gastroenterology 898 2004;127:1123–1130 169. Sanyal AJ, Freedman AM, Luketic VA, et al. Transjugular 152. Jenkins SA, Shields R, Davies M, et al. A multicentre intrahepatic portosystemic shunts for patients with active randomised trial comparing octreotide and injection scler- variceal hemorrhage unresponsive to sclerotherapy. Gastro- otherapy in the management and outcome of acute variceal enterology 1996;111:138–146 haemorrhage. Gut 1997;41:526–533 170. Bureau C, Garcia-Pagan JC, Otal P, et al. Improved clinical 153. Escorsell A, Bandi JC, Andreu V, et al. Desensitization to outcome using polytetrafluoroethylene-coated stents for the effects of intravenous octreotide in cirrhotic patients with Trends Pharmacol Sci: results of a randomized study. portal hypertension. Gastroenterology 2001;120:161–169 Gastroenterology 2004;126:469–475 154. Besson I, Ingrand P, Person B, et al. Sclerotherapy with or 171. Rossi P, Salvatori FM, Fanelli F, et al. Polytetrafluoroethy- without octreotide for acute variceal bleeding. N Engl J Med lene-covered nitinol stent-graft for transjugular intrahepatic 1995;333:555–560 portosystemic shunt creation: 3-year experience. Radiology 155. Sung JJ, Chung SC, Yung MY, et al. Prospective randomised 2004;231:820–830 study of effect of octreotide on rebleeding from oesophageal 172. Ockenga J, Kroencke TJ, Schuetz T, et al. Covered varices after endoscopic ligation. Lancet 1995;346:1666– transjugular intrahepatic portosystemic stents maintain lower 1669 portal pressure and require fewer reinterventions than 156. Conn HO, Ramsby GR, Storer EH, et al. Intraarterial uncovered stents. Scand J Gastroenterol 2004;39:994–999 vasopressin in the treatment of upper gastrointestinal 173. Marchesini G, Fabbri A, Bianchi G, Brizi M, Zoli M. Zinc hemorrhage: a prospective, controlled clinical trial. Gastro- supplementation and amino acid-nitrogen metabolism in enterology 1975;68:211–221 patients with advanced cirrhosis. Hepatology 1996;23:1084– 157. Bosch J, Groszmann RJ, Garcia-Pagan JC, et al. Association 1092 of transdermal nitroglycerin to vasopressin infusion in the 174. Kjaergard LL, Liu J, Als-Nielsen B, Gluud C. Artificial and treatment of variceal hemorrhage: a placebo-controlled bioartificial support systems for acute and acute-on-chronic clinical trial. Hepatology 1989;10:962–968 liver failure: a systematic review. JAMA 2003;289:217–222 158. Gimson AE, Westaby D, Hegarty J, Watson A, Williams R. 175. Blei AT, Cordoba J. Hepatic encephalopathy. Am J A randomized trial of vasopressin and vasopressin plus Gastroenterol 2001;96:1968–1976 nitroglycerin in the control of acute variceal hemorrhage. 176. Madoff DC, Perez-Young IV, Wallace MJ, Skolkin MD, Hepatology 1986;6:410–413 Toombs BD. Management of Trends Pharmacol Sci–related 159. Soderlund C, Magnusson I, Torngren S, Lundell L. refractory hepatic encephalopathy with reduced Wallgraft Terlipressin (triglycyl-lysine vasopressin) controls acute bleed- endoprostheses. J Vasc Interv Radiol 2003;14:369–374 ing oesophageal varices: a double-blind, randomized, placebo- 177. Kerlan RK Jr, LaBerge JM, Baker EL, et al. Successful controlled trial. Scand J Gastroenterol 1990;25:622–630 reversal of hepatic encephalopathy with intentional occlusion 160. Garcia-Compean D, Blanc P, Bories JM, et al. Treatment of of transjugular intrahepatic portosystemic shunts. J Vasc active gastroesophageal variceal bleeding with terlipressin or Interv Radiol 1995;6:917–921 260 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006

178. Shioyama Y, Matsueda K, Horihata K, et al. Post-Trends common but rarely recognized syndrome. Ann Intern Med Pharmacol Sci hepatic encephalopathy treated by occlusion 1964;60:568–580 balloon-assisted retrograde embolization of a coexisting 195. Guarner C, Soriano G. Spontaneous bacterial peritonitis. spontaneous splenorenal shunt. Cardiovasc Intervent Radiol Semin Liver Dis 1997;17:203–217 1996;19:53–55 196. McHutchison J, Runyon BA. Spontaneous bacterial perito- 179. Bernard B, Cadranel JF, Valla D, Escolano S, Jarlier V, nitis. In: Surawicz CM, Owen R, eds. Gastrointestinal and Opolon P. Prognostic significance of bacterial infection in Hepatic Infections. Philadelphia, PA: WB Saunders; 1994: bleeding cirrhotic patients: a prospective study. Gastroenter- 455–475 ology 1995;108:1828–1834 197. Runyon BA, Hoefs JC. Culture-negative neutrocytic ascites: 180. Goulis J, Armonis A, Patch D, Sabin C, Greenslade L, a variant of spontaneous bacterial peritonitis. Hepatology Burroughs AK. Bacterial infection is independently associated 1984;4:1209–1211 with failure to control bleeding in cirrhotic patients with 198. Chu CM, Chang KY, Liaw YF. Prevalence and prognostic gastrointestinal hemorrhage. Hepatology 1998;27:1207–1212 significance of bacterascites in cirrhosis with ascites. Dig Dis 181. Soriano G, Guarner C, Tomas A, et al. Norfloxacin prevents Sci 1995;40:561–565 bacterial infection in cirrhotics with gastrointestinal hemor- 199. Cabrera J, Arroyo V, Ballesta AM, et al. Aminoglycoside rhage. Gastroenterology 1992;103:1267–1272 nephrotoxicity in cirrhosis: value of urinary beta 2- 182. Blaise M, Pateron D, Trinchet JC, Levacher S, Beaugrand microglobulin to discriminate functional renal failure M, Pourriat JL. Systemic antibiotic therapy prevents from acute tubular damage. Gastroenterology 1982;82: bacterial infection in cirrhotic patients with gastrointestinal 97–105 hemorrhage. Hepatology 1994;20(1 Pt 1):34–38 200. Felisart J, Rimola A, Arroyo V, et al. Cefotaxime is more 183. Hsieh WJ, Lin HC, Hwang SJ, et al. The effect of effective than is ampicillin-tobramycin in cirrhotics with ciprofloxacin in the prevention of bacterial infection in severe infections. Hepatology 1985;5:457–462 patients with cirrhosis after upper gastrointestinal bleeding. 201. Runyon BA, McHutchison JG, Antillon MR, Akriviadis Am J Gastroenterol 1998;93:962–966 EA, Montano AA. Short-course versus long-course anti- 184. Pauwels A, Mostefa-Kara N, Debenes B, Degoutte E, Levy biotic treatment of spontaneous bacterial peritonitis: a VG. Systemic antibiotic prophylaxis after gastrointestinal randomized controlled study of 100 patients. Gastroenter- hemorrhage in cirrhotic patients with a high risk of infection. ology 1991;100:1737–1742 Hepatology 1996;24:802–806 202. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous 185. Bernard B, Grange JD, Khac EN, Amiot X, Opolon P, albumin on renal impairment and mortality in patients with Poynard T. Antibiotic prophylaxis for the prevention of cirrhosis and spontaneous bacterial peritonitis. N Engl J Med bacterial infections in cirrhotic patients with gastrointest- 1999;341:403–409 inal bleeding: a meta-analysis. Hepatology 1999;29:1655– 203. Fernandez J, Monteagudo J, Bargallo X, et al. A randomized 1661 unblinded pilot study comparing albumin versus hydro- 186. Toledo C, Salmeron JM, Rimola A, et al. Spontaneous xyethyl starch in spontaneous bacterial peritonitis. Hepatol- bacterial peritonitis in cirrhosis: predictive factors of infec- ogy 2005;42:627–634 tion resolution and survival in patients treated with 204. Ochs A, Rossle M, Haag K, et al. The transjugular cefotaxime. Hepatology 1993;17:251–257 intrahepatic portosystemic stent-shunt procedure for refrac- 187. Follo A, Llovet JM, Navasa M, et al. Renal impairment tory ascites. N Engl J Med 1995;332:1192–1197 after spontaneous bacterial peritonitis in cirrhosis: incidence, 205. Choudhury J, Sanyal AJ. Treatment of ascites. Curr Treat clinical course, predictive factors and prognosis. Hepatology Options Gastroenterol 2003;6:481–491 1994;20:1495–1501 206. Luca A, Garcia-Pagan JC, Bosch J, et al. Beneficial effects of 188. Navasa M, Follo A, Filella X, et al. Tumor necrosis intravenous albumin infusion on the hemodynamic and factor and interleukin-6 in spontaneous bacterial peritonitis humoral changes after total paracentesis. Hepatology 1995; in cirrhosis: relationship with the development of renal im- 22:753–758 pairment and mortality. Hepatology 1998;27:1227–1232 207. Dagher L, Moore K. The hepatorenal syndrome. Gut 2001; 189. Garcia-Tsao G, Albillos A, Barden GE, West AB. Bacterial 49:729–737 translocation in acute and chronic portal hypertension. 208. Gines P, Cardenas A, Arroyo V, Rodes J. Management of Hepatology 1993;17:1081–1085 cirrhosis and ascites. N Engl J Med 2004;350:1646–1654 190. Llovet JM, Bartoli R, March F, et al. Translocated intestinal 209. Gines P, Guevara M, Arroyo V, Rodes J. Hepatorenal bacteria cause spontaneousbacterial peritonitis in cirrhotic rats: syndrome. Lancet 2003;362:1819–1827 molecular epidemiologic evidence. J Hepatol 1998;28:307– 210. Arroyo V, Gines P, Gerbes AL, et al. Definition and 313 diagnostic criteria of refractory ascites and hepatorenal 191. Tito L, Rimola A, Gines P, Llach J, Arroyo V, Rodes J. syndrome in cirrhosis. International Ascites Club. Hepatol- Recurrence of spontaneous bacterial peritonitis in cirrhosis: ogy 1996;23:164–176 frequency and predictive factors. Hepatology 1988;8:27–31 211. Moller S, Bendtsen F, Henriksen JH. Pathophysiological 192. Andreu M, Sola R, Sitges-Serra A, et al. Risk factors for basis of pharmacotherapy in the hepatorenal syndrome. spontaneous bacterial peritonitis in cirrhotic patients with Scand J Gastroenterol 2005;40:491–500 ascites. Gastroenterology 1993;104:1133–1138 212. Laffi G, La Villa G, Gentilini P. Pathogenesis and manage- 193. Runyon BA. Low-protein-concentration ascitic fluid is ment of the hepatorenal syndrome. Semin Liver Dis 1994;14: predisposed to spontaneous bacterial peritonitis. Gastro- 71–81 enterology 1986;91:1343–1346 213. Arroyo V, Guevara M, Gines P. Hepatorenal syndrome in 194. Conn HO. Spontaneous peritonitis and bacteremia in cirrhosis: pathogenesis and treatment. Gastroenterology Laennec’s cirrhosis caused by enteric organisms. A relatively 2002;122:1658–1676 INTENSIVE MANAGEMENT OF HEPATIC FAILURE/RINELLA, SANYAL 261

214. Maurizio R, Eugenio C, Roberto PR. Results of sclerother- cirrhosis and type 1 hepatorenal syndrome. Hepatology apy for bleeding esophageal varices in patients with 2004;40:55–64 schistosomal liver disease: a retrospective study. Hepatogas- 218. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, troenterology 2000;47:424–428 ter Borg PC. A model to predict poor survival in patients 215. Ortega R, Gines P, Uriz J, et al. Terlipressin therapy with undergoing transjugular intrahepatic portosystemic shunts. and without albumin for patients with hepatorenal syn- Hepatology 2000;31:864–871 drome: results of a prospective, nonrandomized study. 219. Wiesner RH, McDiarmid SV, Kamath PS, et al. MELD Hepatology 2002;36(4 Pt 1):941–948 and PELD: application of survival models to liver allocation. 216. Angeli P, Volpin R, Gerunda G, et al. Reversal of type 1 Liver Transpl 2001;7:567–580 hepatorenal syndrome with the administration of midodrine 220. Wiesner R, Edwards E, Freeman R, et al. Model for end- and octreotide. Hepatology 1999;29:1690–1697 stage liver disease (MELD) and allocation of donor livers. 217. Wong F, Pantea L, Sniderman K. Midodrine, octreotide, Gastroenterology 2003;124:91–96 albumin, and Trends Pharmacol Sci in selected patients with