Intensive Management of Hepatic Failure

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1 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 complications 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 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 end-stage decompensated cirrhosis. Both sides of this spectrum present clinical challenges that involve many organ systems. Although both sides in acute and chronic liver failure can have a poor prognosis, careful and comprehensive intensive care can improve outcome and bridge eligible patients to liver transplantation. Because acute and chronic liver failure are very distinct clinical entities, they will be discussed separately. ACUTE LIVER FAILURE Acute liver failure (ALF) is a rapidly progressive, often fatal syndrome characterized by jaundice, encephalopathy, and coagulopathy leading to multiorgan failure in a patient with no prior history of liver disease. 1,2 In recent years, advancements in supportive care have improved survival and provided a more effective bridge to transplantation. Although ALF remains one of the most acute serious illnesses, thoughtful intensive management can optimize the patient s chances for spontaneous hepatic regeneration or a successful liver transplant. 3 When possible, etiology-targeted therapy should be initiated (Table 1). The goal of management should be focused on the prevention of systemic infection, multiorgan failure, hepatic encephalopathy (HE), and ultimately the development of brain edema. 4 6 At this time liver transplantation is the only definitive therapy for those who fulfill criteria for poor prognosis 7 9 (Table 2). The challenge to the clinician is selection of patients for transplant that have low likelihood of spontaneous survival but are not too ill to benefit from transplantation. The principles of management of ALF are reviewed here: INITIAL EVALUATION AND MANAGEMENT Early diagnosis and identification of the subject that is unlikely to improve spontaneously constitute a critical first step in the management of ALF. The initial triage 1 Division of Hepatology, Northwestern University, Chicago, Illinois; 2 Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia. Address for correspondence and reprint requests: Arun Sanyal, M.D., Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University, MCV Box , Richmond, VA Non-pulmonary Critical Care: Managing Multisystem Critical Illness;GuestEditor,CurtisN.Sessler,M.D. Semin Respir Crit Care Med 2006;27: Copyright # 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) DOI /s ISSN

2 242 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER Table 1 Etiology Etiology-Targeted Therapy TOXIC Acetaminophen Amanita poisoning VIRAL Herpes simplex virus Acute heptatitis B METABOLIC Wilson s disease Autoimmune hepatitis VASCULAR Acute Budd-Chiari syndrome PREGNANCY Acute fatty liver of pregnancy/hellp Potential Therapies N-acetyl cysteine Penicillin and silibinin Acyclovir Antivirals? Transplant Corticosteroids Directed thrombolysis, transjugular intrahepatic portosystemic shunt Urgent delivery HELLP, hemolysis elevated liver enzymes low platelets. of a patient with acute liver injury to an intensive care unit (ICU) is based on the presence of altered mental status and the degree of coagulopathy. It is imperative toadmitmostsubjectswithacuteliverinjurywithan international normalized ratio (INR) > 1.5 and all subjects with mental status changes. Rapid deterioration can occur and is often irreversible in the patient with ALF. It is therefore imperative that decisions regarding prognosis and appropriateness for liver transplant be made early, and potentially suitable patients should be referred to a liver transplant center early in the evaluation process. The management of patients in liver failure requires a multidisciplinary approach involving hepatologists, transplant surgeons, intensivists, and other subspecialists. The importance of a thorough physical exam Table 2 King s College Criteria for Acute Liver Failure Acetaminophen induced Arterial blood ph < 7.3 (regardless of degree of encephalopathy) If no acidosis then all three of the below criteria: Prothrombin time > 100 seconds Serum Creatinine > 2.5 mg/dl Grade 3 or 4 encephalopathy Nonacetaminophen induced Prothrombin time > 100 seconds If prothrombin time < 100 seconds, then any of the below criteria (regardless of degree of encephalopathy): Drug-induced, non-a, non-b, halothane hepatitis Time from jaundice to encephalopathy > 7 days Age < 10 or > 40 years Prothrombin > 50 seconds Bilirubin > 17.5 mg/dl and an accurate history cannot be overemphasized because both treatment and prognosis are significantly affected by the underlying etiology. A detailed account of the psychiatric history, including suicidal ideation and family support, is essential to assess suitability for transplantation. The timing of the psychiatric evaluation is of particular importance, given the rapid deterioration in mental status that occurs in such patients. DISEASE-TARGETED THERAPY A thorough discussion of the differential diagnosis of ALF is beyond the scope of this review; however, Table 1 provides a summary of common etiologies of ALF for which potential therapies exist. Only acetaminophen will be discussed in more detail because it is the most common etiology of liver failure in the United States and has an effective antidote. Acetaminophen Idiopathic and drug-related liver injuries are the most common causes of ALF in the United States. 10 Of the drug-related causes, acetaminophen overdose is the most common cause of ALF in the United Kingdom and United States. Overdose can be either intentional or unintentional The patient, family, and close contacts must be questioned about regular alcohol use, dieting, diet pills, medications, or recent illness that may have resulted in poor nutrition. These factors greatly affect toxicity either through upregulating cytochrome p450 (alcohol and other drugs) promoting the formation of toxic intermediates, or through glutathione depletion. Such details are important because as little as 2.6 to 4.0 g of acetaminophen can lead to liver failure in this setting It is worth noting that, at the time of presentation, a patient with acetaminophen-induced liver failure may have undetectable blood levels of acetaminophen. This is particularly true when the toxicity manifests itself several days after ingestion of acetaminophen for therapeutic purposes in a susceptible subject. However, in the majority of cases, detectable acetaminophen levels are present at the time of presentation. When acetaminophen overdose is confirmed, N-acetylcysteine (NAC) must be initiated in a timely manner, ideally within 16 hours of ingestion, to have a significant impact on survival. NAC decreases injury through enhancement of glutathione synthesis resulting in less formation of acetaminophen s hepatotoxic intermediate. 18,19 Even if the patient is delayed in reaching the hospital or the diagnosis is not forthcoming, there is evidence that late administration of NAC can be beneficial. 20 NAC may also improve outcome through its effects on microcirculatory function. A large multicenter study (the ALF study group) is currently addressing the utility of NAC in nonacetaminophen-induced ALF.

3 INTENSIVEMANAGEMENT OFHEPATICFAILURE/RINELLA, SANYAL 243 Table 3 Acute Liver Failure: General Management Guidelines On Admission Daily Tid Hourly If Indicated Monitoring IV access, CVP and arterial line, Foley catheter Blood sugar Mental status Mechanical intubation, ICP monitoring Thorough history and physical Interview family members Laboratories Liver panel, renal panel, CBC, PT, Hep A,B,C serologies, HSV, CMV, EBV, ceruloplasmin, ANA, anti-sm Ab, SPEP, HIV, acetaminophen level, toxicology screen, cosyntropin stimulation test, TSH, blood type, blood cultures Basic laboratories, AFP, arterial ammonia (or more if mental status deteriorating phosphate, factor V level Blood gas Changes in ICP monitor 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, cytomegalovirus; CT, computed tomography; CVP, central venous pressure; EBV, Epstein-Barr virus; HSV, herpes simplex virus; HIV, human immunodeficiency virus; ICP, intracranial pressure; IV, intravenous; PT, prothrombin time; SPEP, serum protein electrophoresis; TSH, thyroid stimulating hormone; US, ultrasound. MONITORING AND GENERAL GUIDELINES Acute hepatic dysfunction has profound effects on many organs. Therefore, one must remain cognizant of the ramifications of specific therapies on other systems. The mental status must be documented several times daily, in addition to frequent assessment of hepatic synthetic function and blood glucose (Table 3). Although a liver biopsy may be helpful if the diagnosis is in question, it can be unreliable in predicting outcome and is risky given the presence of underlying coagulopathy. 21 Low serum phosphate and elevated a fetoprotein can be encouraging signs of hepatic regeneration. 22,23 In a retrospective analysis of ALF patients, 74% of patients with phosphate levels < 2.5 were alive at 1 week, in contrast to none in those with a serum phosphate > Coagulopathy in ALF does not usually require correction unless an invasive procedure is planned or overt bleeding is present because the use of fresh frozen plasma (FFP) can mask deterioration of liver function. A common indication for the correction of coagulopathy is placement of a central line. Traditionally, FFP and cryoprecipitates have been used for the correction of coagulopathy in subjects with ALF. This is only partially effective in correcting coagulopathy and its effects are short-lived. It is also associated with a risk of transmitting cytomegalovirus infection and may contribute to volume overload and pulmonary edema, especially when renal function begins to deteriorate. Alternate approaches include the use of plasmapheresis where a volume of plasma equal to the amount infused is removed to prevent volume overload. Recently, recombinant factor VII (40 mg/kg) has been used in conjunction with FFP to rapidly correct coagulopathy prior to either intracranial pressure monitor or central line placement in patients with ALF. 25 MECHANICAL VENTILATION Mechanical ventilation should be initiated once encephalopathy deteriorates to grade 3 (West Haven criteria) to protect the airway. 26,27 In addition to preventing aspiration in the patient with compromised mental status, intubation and sedatives help control agitation, which can lead to surges in intracranial pressure. Patients with encephalopathy beyond grade 3 are very difficult to manage without intubation and sedation. 28 Sedation is best achieved with a short-acting sedative alone or in combination with a short-acting narcotic. Recent evidence supports the use of propofol for this purpose. In a small study, propofol was given to seven patients with ALF and profound encephalopathy. Intracranial pressure (ICP) remained normal in six of

4 244 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER seven patients with ALF given propofol at 50 mg/kg/ min, suggesting propofol may have independent beneficial 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 patients 30 ; however, the theoretical risk of increasing the incidence of pneumonia has not been studied in this population. PREVENTION AND MANAGEMENT OF COMPLICATIONS Circulatory Dysfunction Derangements in circulatory function manifest early in ALF and are often progressive. They are characterized by generalized vasodilation, increased cardiac output, decreased systemic vascular resistance, and a low mean arterial pressure (MAP) It is challenging to distinguish this clinical picture from the hemodynamics of sepsis, particularly given that infection is common and often a fatal complication. 34 Factors such as adrenal insufficiency also complicate management by making the vasculature less responsive to vasopressive agents. 35,36 In general terms, fluids and vasopressors should be used to maintain adequate cerebral perfusion pressure (CPP) (50 mm Hg to 65 mm Hg) while avoiding cerebral hyperemia from hyperperfusion. 37,38 Because the circulatory disturbance in ALF is characterized by vasodilation and increased cardiac output, norepinephrine is frequently the vasopressor of choice. Infection Patients with ALF are particularly susceptible to severe infection due to many immunological defects such as defective phagocytic function and decreased complement levels Bacterial or fungal sepsis is a frequent cause of death in this population. Much like other immunocompromised hosts, their response to infection is atypical in that signs such as fever or leukocytosis are absent in 30% of cases. 43 Thus sepsis is both frequent and difficult to diagnose in subjects with ALF. In a prospective study of 887 patients with ALF, one or more bacterial infections occurred in 37.8%; however, an 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 frequent pathogens. 45 Overall, pneumonias make up 50% of bacterial infections in ALF with bacteremia and urinary tract infections occurring in 20 and 25%, Figure 1 The effect of antibiotic prophylaxis on the prevalence of documented infection patients with acute liver failure. (Adapted from Salmeron et al. 47 ) respectively. These infections presented at a median of 5, 3, and 2 days after the onset of ALF. 44 Given the frequency of both gram-negative and gram-positive infections in this population, broad spectrum antibiotic coverage should be administered avoiding aminoglycosides due to their nephrotoxicity. 34 Although no randomized controlled trials have demonstrated improved survival with prophylactic antibiotics, parenteral antibiotics are associated with a lower incidence of infection 46 (Fig. 1). 47 Given these data, prophylactic broad-spectrum antibiotics seem justifiable given that uncontrolled infection in such patients is often catastrophic. 48,49 Systemic Inflammatory Response Syndrome Even in the absence of documented infection, systemic inflammatory response syndrome (SIRS) is common in those with ALF and is likely due to a surge of cytokine release. 50 In a study from King s College, 57% of 887 patients with ALF developed SIRS. The presence of SIRS on admission was independently associated with more severe illness, worsening of encephalopathy, and subsequent death. In those patients that were infected (54%), mortality increased with each additional component of SIRS. At this point it remains unclear how additional infection contributes or which component of the observed inflammatory response originates from humoral factors released by the necrotic liver. 34,46,51 Adrenocortical Insufficiency Adrenocortical insufficiency can worsen hyperdynamic cardiovascular collapse typical of ALF or septic shock. 52 This should be considered when the patient fails

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

6 246 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER Figure 3 Proposed algorithm for the use of an intracranial pressure monitor. markers of brain cell dysfunction and damage such as s100-b and neuron-specific enolase (NSE) have also been evaluated as potential predictors of impending herniation in the setting of ALF and acute on chronic liver failure with negative results. 62 Currently, no serum markers of brain cell dysfunction reliably demonstrate neurological injury and poor outcome. Unfortunately, it can be difficult to predict which patients are likely to develop elevated ICP. Clinical signs such as arterial hypertension, fever, and agitation can precede episodes of severe ICH; however, these are not reliable predictors because elevated ICP is often clinically silent. 63 Although a computed tomographic (CT) 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. INTRACRANIAL PRESSURE MONITORING A significant clinical challenge in the management of ALFisthedecisiontoplaceanICPmonitor.Thereare no strict guidelines related to the use of these monitors and experience across institutions is highly variable. Noninvasive techniques have not proven to be beneficial and direct ICP monitoring is the only reliable modality for the measurement of ICP. The benefit that can be derived from ICP monitoring is twofold. First, it allows for the early detection and treatment of ICH because it can be clinically silent. 63 Second, it can provide invaluable information about the likelihood of neurological recovery when deciding whether to proceed with liver transplantation, such as when CPP is persistently low. Sustained CPP < 40 mm Hg predicts a high likelihood of ischemic brain injury that typically results in a poor neurological outcome after transplantation. 64,65 Figure 3 proposes an algorithm for the use of ICP monitors in ALF. Although treatments aimed at reducing ICP can be used without an ICP monitor, an accurate ICP reading permits targeted therapy to optimize CPP and detect abrupt surges in pressure that necessitate additional therapy. Concomitant measurement of jugular bulb oxygen saturation, 32,66 which allows measurement of brain oxygen utilization, can also be useful in the management of these patients. 32 Jugular bulb oxygen saturation > 80% or < 60% predicts elevation in ICP with good sensitivity and specificity. 31 Jugulovenous O 2 saturations < 50% may herald an increase in anaerobic cerebral glycolysis, increased lactate:pyruvate ratio, and worsening cerebral edema. 67 When and in Whom to Insert an Intracranial Pressure Monitor To justify the risks of ICP monitor placement, the monitor needs to be placed under controlled circumstances, when increased ICP is likely to rise but before uncontrolled ICH and herniation occur. ICP monitoring should be considered for mechanically ventilated patients with grade 3 or 4 encephalopathy with poor prognosis (Table 2) but who are otherwise good candidates for liver transplant (Fig. 3). Other predictors of increased ICP such as arterial ammonia > 150 mmol/l could be used to time monitor placement. In those with poor prognosis without orthopedic liver transplant (OLT), ICP monitoring can guide therapy and prevent surges in ICH before and during OLT. Risks of Intracranial Pressure Monitoring As with all interventions, the risks of ICP monitor placement need to be balanced against the accuracy and usefulness of the information to be gained. No randomized, controlled trial is available to compare different

7 INTENSIVEMANAGEMENT OFHEPATICFAILURE/RINELLA, SANYAL 247 catheters in the setting of ALF. Types of catheters include epidural, subdural, parenchymal, and intraventricular catheters. Blei et al performed a survey of transplant centers across the United States. They estimated that 20% of ICP monitoring resulted in intracranial bleeding. Epidural catheters had the lowest rate of bleeding complications (3.8%) and subdural and parenchymal catheters the highest; 20% and 22%, respectively. 68 A recent multicenter study from the ALF study group showed that ICP monitors were only used in 92/332 patients (28%) with ALF and severe encephalopathy; however, the frequency of monitoring differed between centers. Ten percent had intracranial bleeding as a result of the ICP monitor. In two of these patients, ICP monitoring was directly associated with the patient s death. 69 Although the risk of complications is greater, 70 subdural catheters give a more reliable estimate of ICP than epidural catheters. 68 Bleeding complications can be decreased significantly with the use of recombinant factor rviia given immediately before the procedure. 25 The frequency of factor VII dosing was variable in this study; however, as a group all patients that received factor VII normalized their prothrombin time (PT) and were able to have ICP monitors placed (compared with 38% in the FFP alone group). The ideal initial dose and subsequent doses of factor VII necessitates further study. 71 The data show that ICP monitoring can be an effective tool for managing elevated intracranial pressure; however, ICP monitors have not been shown to improve survival. Currently there is no consensus about the use of ICP monitoring or whether the more accurate but higher-risk subdural catheters or the less accurate but safer epidural catheter should be used. Individual centers will continue to use what they are comfortable with; however, their decision may be influenced by the decreased availability of epidural catheters. Prevention and Treatment of Increased Intracranial Pressure Routine measures such as elevation of the head of the bed to 30 degrees, 55 sedation, minimal stimulation, and mechanical ventilation to minimize cerebral stimulation should be adhered to whenever possible. The management should be focused on maintaining an adequate CPP (> 50 mm Hg) while minimizing elevations in ICP (< 20 mm Hg). Blood pressure should be maintained to achieve a CPP between 50 and 65 mm Hg. Prolonged CPP below 50 mm Hg in the setting of ICH or an ICP greater than 40 mm Hg is associated with poor outcome. 65 HYPERTONIC SALINE The use of hypertonic saline is thought to help restore the osmotic gradient across the astrocyte membrane. A randomized, controlled trial recently demonstrated that induction and maintenance of hypernatremia (145 to 155 mmol/l) in patients with grade 3 or 4 encephalopathy resulted in a decreased incidence and severity of ICH. 72 Other techniques to reduce brain water accumulation through the reduction of arterial ammonia remain under investigation MANNITOL Mannitol administration leads to increased plasma osmolality in brain capillaries, resulting in movement of water out of the brain according to Starling s law. It has been shown to decrease episodes of cerebral edema and result in improved survival in a cohort of patients with ALF (47.1 and 5.9%, respectively, p ¼.008). 76 Its use, however, is limited in renal failure and can lead to a paradoxical increase in brain swelling if osmolality is not controlled. If more than two doses are to be used, plasma osmolality must be checked to assure that it remains < 320 Osm/L. HYPERVENTILATION Hyperventilation is an effective technique to decrease cerebral blood flow (CBF) and ICP. It does so through precapillary hypocapnic vasoconstriction and helps restore CBF autoregulation. 61,77 79 Although prophylactic hyperventilation appears to be ineffective in preventing the development of ICH, 77 it can be useful in controlling acute surges in ICP. INDOMETHACIN Indomethacin leads to cerebral vasoconstriction effects via altering cerebral temperature and extracellular ph and inhibition of the endothelial cyclooxygenase pathway. 80 Its effectiveness has been proven in an animal model 81 and in a small cohort of patients with ALF. 82 However, due to its multiple systemic side effects in patients with ALF, its routine use cannot be supported. THIOPENTAL SODIUM In a small, uncontrolled study, thiopental sodium was effective in reducing ICP. 83 Unfortunately, its use is associated with significant hemodynamic derangements that may necessitate escalation of vasopressor or inotropic support. Thus thiopental use should be reserved for surges of ICH unresponsive to standard medical therapy. HYPOTHERMIA Moderate hypothermia (32 to 33 C) in animal models of ALF has been effective in improving encephalopathy and reducing brain water. 84,85 Clinical studies of hypothermia have also shown significant reduction in ICP. Jalan et al were able to demonstrate that cooling patients with refractory ICH to 32 C decreased ICP to < 20 mm Hg. Subsequently they demonstrated a reciprocal increase in ICP with rewarming. 86 Since this study, the same and other groups have also shown that moderate

8 248 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER hypothermia is effective in the prevention of ICH in ALF, as a bridge to transplant, 87 and during liver transplantation 88 to prevent surges in ICP. The mechanism of action is presumed to be multifactorial but includes reduction of CBF, cerebrospinal fluid (CSF) ammonia, and extracellular glutamate concentrations. Although hypothermia may be beneficial to the brain in decreasing ICP, it also impacts coagulation and may promote infection and cardiac rhythm disturbances. It is difficult to know, however, if hypothermia exacerbates such factors because these are well-known complications of liver failure per se. Some have raised concern that hypothermia may impair hepatic regeneration and commit patients to transplant. 89,90 The degree to which hypothermia influences such factors needs to be addressed in a well-designed randomized, controlled trial before its use in routine practice can be justified. LIVER ASSIST DEVICES Liver assist devices are of two general types: biological devices and artificial devices. Biological devices use living hepatocytes to replace liver function, whereas artificial devices such as the molecular absorbent recirculating system (MARS) aim to remove injurious substances 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 liver assist device]). 92 A large multicenter study of BAL in ALF resulted in no survival advantage. 93 In a small randomized controlled trial, ELAD resulted in less severity of encephalopathy without improvement in survival. 94 Overall, the data on bioartificial liver devices are disappointing in that they are quite costly and have not resulted in improved synthetic function or survival. 95 MARS removes free and albumin-bound toxins via a polysulfone membrane. 96,97 In contrast to bioartificial devices, MARS has mainly been tested in acute on chronic liver failure (AoCLF). Two small randomized clinical trials have shown improvement in encephalopathy and increased survival. 98,99 MARS also appears to be effective in ameliorating renal function in hepatorenal syndrome and hemodynamics through increasing systemic vascular resistance (SVR). 100 Although not a primary end point, survival was improved in a prospective, randomized, controlled trial of MARS in liver failure. 99 The study was terminated prematurely due to perceived ethical considerations. Unfortunately, had as little as one or two deaths occurred in the MARS group the difference in survival would have no longer been statistically significant. The results of this trial would 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 over standard medical therapy. 101 MARS appears to be well tolerated; however, a fair number of patients developed thrombocytopenia; thus its use should be restricted in patients with DIC. 102 LIVER TRANSPLANTATION FOR ACUTE LIVER FAILURE Because the mortality of patients with ALF is almost universal once they meet criteria for poor prognosis (Table 2), they receive the utmost priority. The Status 1 classification has remained from the former process of organ allocation. To receive this listing, the patient must have no prior history of liver disease and fulfill criteria for ALF with poor prognosis. Intensive medical supportive care is geared toward the avoidance of complications that could preclude transplant. The decision to proceed with transplantation 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 stability, compliance, and wishes. Psychiatric stability and strong social support are essential to a successful transplant. It is imperative to accurately document active drug or alcohol abuse, suicidal ideation, or history of a previous suicide attempt because these are examples of potential contraindications to transplant. ACUTE OR CHRONIC LIVER FAILURE GENERAL CONSIDERATIONS Critically ill patients with cirrhosis admitted to the ICU have poor survival even if they survive the initial ICU stay. Mortality can reach 100% in cases complicated by septic shock Acute hepatic decompensation in a patient with chronic liver disease (AoCLF) is most commonly precipitated by gastrointestinal bleeding or infection. As a result of this, major functions of the liver such as the synthesis of key proteins, detoxification, and metabolic regulation are impaired to various degrees. The imbalance created by the physiological needs of the critically ill patient and the liver s limited ability to perform key functions leads to life-threatening complications such as renal failure, infection, HE, cholestasis, ascites, and bleeding. An important step in the initial management of patients with AoCLF is the identification and treatment of the precipitating factor that led to acute decompensation. Patients admitted to the ICU with AoCLF should be managed with a simultaneous multifaceted approach that will bridge eligible patients to transplantation and improve short-term survival in nontransplant candidates. PORTAL HYPERTENSIVE BLEEDING Portal hypertensive hemorrhage is a serious and frequent complication of advanced cirrhosis Bleeding can

9 Table 4 Child-Pugh Score Score Bilirubin/mmol/L Albumin/g/L INR Ascites Encephalopathy 1 < 2 > 3.5 < 1.3 Absent Mild I/II 3 > 3 < 2.7 > 1.5 > Moderate III/IV INTENSIVEMANAGEMENT OFHEPATICFAILURE/RINELLA, SANYAL 249 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 hypertensive gastropathy, or less commonly from portal colopathy, duodenal or rectal varices. A successful outcome depends on accurate diagnosis, prompt resuscitation, hemodynamic support, management of complications, and control of active bleeding. Clinical factors associated with bleeding include deterioration of liver function, portal vein thrombosis, hepatocellular carcinoma, and ongoing alcohol use. 110 In cirrhosis, portal hypertension is the result of the combined effects of increased portal venous inflow and an increased resistance to that flow. 111 The corrected sinusoidal pressure gradient is inversely associated with risk of bleeding as well as outcome after bleeding A hepatic venous pressure gradient (HVPG) of 12 mm Hg is a threshold value, with variceal hemorrhage occurring above this level 112 and therapeutic intervention aiming at a reduction below this value. 115,116 However, many studies have shown that if portal pressure is reduced in a sustained manner by 20%, the risk of bleeding is low (10% at 2 years), even if the HVPG remains above 12 mm Hg. 109,117 Acute variceal hemorrhage (AVH) occurs in 30 to 35% of patients with cirrhosis and is associated with significant mortality. A recent retrospective analysis reported in-hospital, 6-week, and overall mortality rates of 14.2%, 17.5%, and 33.5%, respectively, suggesting improved therapy of AVH has impacted survival. 118 Oneyear survival following a variceal bleed greatly depends on the severity of liver disease assessed by the Child-Pugh classification (Table 4). Mortality after a variceal hemorrhage is 5% and 50% in Child-Pugh A and C cirrhotic patients, respectively, 119 and 70% of those that survive will rebleed. 110,120 A hepatic venous pressure gradient > 20 mm Hg after an acute bleed is an independent predictor of poor outcome. Such measurements may be useful to assess prognosis and tailor therapy. 114 The management of patients with gastroesophageal varices involves (1) prevention of the initial bleed (primary prophylaxis is beyond the scope of this review), (2) management of the acute bleed, and (3) prevention of rebleeding (secondary prophylaxis). Variceal Hemorrhage General Considerations Acute hemorrhage typically presents with hematemesis with or without melena or hematochezia. Hemodynamic instability is often present and needs to be addressed with continuous cardiac monitoring and good intravenous access. Knowledge of the central venous pressure is helpful to gauge the adequacy of volume administration without overresuscitating the patient because this can provoke more bleeding from previously decompressed varices or lead to other complications such as acute pulmonary edema. 121,122 Prophylactic endotracheal intubation should be considered in the setting of significant upper gastrointestinal hemorrhage prior to endoscopic intervention for airway protection. Figure 4 proposes an algorithm for the management of AVH. Esophageal Variceal Hemorrhage Mortality associated with AVH has improved in the past decade. 123 Based on data comparing patients presenting with AVH from to , the late cohort experienced a significant decline in mortality at 30 days (20.8% vs 29.6%, p ¼.0001) and at 6 years (69.7% vs 74.5%, p ¼.0001). For patients who survived the first 30 days, survival was slightly better in the late cohort on multivariate analysis (p ¼.01). 124 Spontaneous cessation of bleeding occurs in 50% of patients; however, 60% of these patients will rebleed if there is no intervention. 120 Therapeutic options for the management of variceal hemorrhage include pharmacological therapy (somatostatin, octreotide, vasopressin, or terlipressin), endoscopic therapy (endoscopic band ligation or sclerotherapy), balloon tamponade, transjugular intrahepatic portosystemic shunt (TIPS) or surgical shunts (Fig. 4). Pharmacological treatment is effective and should be initiated on admission to the ICU. Although studies have shown some drugs to be as effective as endoscopic therapy, 125,126 this is controversial; thus we recommend endoscopic intervention in addition to pharmacotherapy for the control of variceal hemorrhage. Gastric Variceal Hemorrhage Gastric varices represent a less frequent, but important source of bleeding in patients with portal hypertension. They are present in up to 57% of patients with esophageal varices secondary to portal hypertension. 127 Less commonly, they are found in the absence of esophageal

10 250 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER Figure 4 Proposed algorithm for the management of acute variceal bleeding. varices. 128 If isolated gastric varices are noted imaging must be performed to exclude splenic vein thrombosis because this is managed with splenectomy. In 117 patients with fundal varices, the size of the vessels, the presence of red spots, and the degree of liver decompensation were predictors of bleeding. 129 Although bleeding from gastric varices is less common than bleeding from esophageal varices, bleeding episodes are often more severe and carry a higher mortality. 128, The management of bleeding from gastric varices differs from that of esophageal varices. Although gastric varices in continuity with esophageal varices can be managed by endoscopic band ligation, isolated varices in the fundus of the stomach are not amenable to either sclerotherapy or band ligation. 133 However, numerous reports have documented the efficacy of cyanoacrylate injections (tissue glue) in achieving hemostasis in bleeding fundic varices. 134,135 Cyanoacrylate glue leads to more rapid variceal obliteration and more effective hemostasis than alcohol injection. 134 Severe complications associated with intravariceal cyanoacrylate glue injection include mediastinitis, CVA, and cardiac and pulmonary vascular glue emboli Recently, pilot studies have found thrombin injections to be another promising approach. 139 Yet another way to control bleeding gastric varices is with special detachable endoscopically placed snares. 140,141 Although there is limited experience with the technique in the United States, the Japanese report success with balloonoccluded retrograde transvenous obliteration (B-RTO) of isolated gastric varices. 142,143 Unfortunately, most of these modalities are not routinely available in the United States. The first-line approach to the control of actively bleeding fundic varices is balloon tamponade. The airway must be protected when this approach is taken. This is, however, a temporizing measure and such varices have a great propensity to rebleed over time. It is therefore reasonable to decompress the portal vein with a TIPS as the definitive procedure of choice in most patients before discharge from the hospital. 144,145 It is often necessary to embolize prominent portosystemic collaterals at the time of TIPS to reduce the risk of bleeding. When this is not done, nonselective b-blockers may be used to reduce the

11 INTENSIVEMANAGEMENT OFHEPATICFAILURE/RINELLA, SANYAL 251 risks of rebleeding, although the data to support such an approach are weak at best. In those with well-preserved liver function, a surgical shunt can also provide longterm relief from bleeding. 146 Portal Hypertensive Gastropathy Portal hypertensive gastropathy (PHG) is a manifestation of portal hypertension. Endoscopically it is characterized by a mosaic mucosal pattern with varying degrees of submucosal hemorrhage. It is often asymptomatic but may lead to chronic transfusion requiring blood loss or acute bleeding (rarely). Although portal gastropathy is more often seen in the setting of gastroesophageal varices, its severity does not correlate with portal pressure. Nevertheless, bleeding is often ameliorated by reduction of portal pressure. Both octreotide and nonselective b-blockade can be helpful in decreasing acute bleeding and the degree of rebleeding from PHG via reduction of portal blood flow In refractory cases, TIPS can be effective at reducing transfusion requirements. 150 THERAPIES TO ACHIEVE HEMOSTASIS Drug Therapy Drug therapy is an integral component of the management of acute portal hypertensive hemorrhage and should be started on presentation. To optimize the effectiveness of drug or endoscopic therapy, clotting abnormalities must be corrected. Target INR and platelet count should be 1.5 and 75, respectively. In the setting of renal failure platelets may be dysfunctional and DDAVP (Desamino-D-Arginine Vasopressin) should be considered. FFP alone or in combination with rfviia can be given to rapidly correct coagulopathy. A recent randomized, clinical trial showed that whengiveninadditiontostandardtherapy,100mg/kg of rfviia may improve control of bleeding in patients with advanced cirrhosis. 151 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 on vasoactive peptides or through the prevention of postprandial hyperemia (blood meal). Octreotide has an excellent safety profile and can be given initially as a subcutaneous bolus of 50 to 100 mg followed by a continuous infusion of 50 mg/h for 3 to 5 days. Although it does decrease portal pressure acutely, these effects appear to be short lived due to rapid tachyphylaxis. 153 Nevertheless, studies have shown a significant decrease in rebleeding after endoscopic therapy in those receiving octreotide infusion. 154,155 Vasopressin reduces splanchnic blood flow in addition to portal pressure. It is effective in controlling variceal hemorrhage; however, its use is limited due to systemic effects such as coronary and mesenteric ischemia. 156 If vasopressin is used in conjunction with nitroglycerin, 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 effective in the treatment of acute variceal bleeding with or without endoscopic therapy and has been shown to reduce mortality. 125,159 It appears to be as effective as vasopressin or endoscopic treatment 126,160 in controlling acute variceal hemorrhage, but is not yet available in the United States. Endoscopic Therapy Endoscopic variceal band ligation (EBL) is currently the preferred endoscopic technique for the management of esophageal varices. It is at least as effective as endoscopic sclerotherapy (EST) but has a superior safety profile and lower complication rate. 133,161,162 EBL also decreases the incidence of bleeding, when given as primary prophylaxis, 163,164 and death 165 from variceal bleeding. Band ligation leads to strangulation and subsequent obliteration of the banded varix. EST involves the injection of a sclerosant (sodium morrhuate, ethanolamine, or polidocanol) into or around a varix. This leads to coagulative necrosis and obliteration of varices in the vicinity of the injection. Complications related to EST tend to occur more frequently and be more severe than with EBL and include esophageal ulceration, stricturing, esophageal perforation, pleural effusion, and sepsis. Despite a higher complication rate, a role still exists for EST. It can be a useful adjunct to EBL in the setting of massive hemorrhage with poor visibility because the location of injection need not be as precise to achieve hemostasis. Regardless of the choice of endoscopic management for acute bleeding, follow-up endoscopy within 1 to 2 weeks for further banding is essential to decrease the risk of rebleeding. EBL should then be continued in the future until variceal obliteration is achieved. Balloon Occlusion Balloon tamponade is effective in the 5 to 10% of patients in which hemostasis cannot be achieved acutely with medical or endoscopic therapy. It successfully stops bleeding from esophagogastric varices through external compression of varices, but rebleeding occurs in 50%. 166 Many types of tubes exist (Sengsten-Blake Tube, Warne Surgical Products, Ltd., Armagh, Ireland, UK; and Linton Tube, Bard Manufacturing, Covington, Georgia, USA) with mild variations; however, in most cases; inflation of the gastric balloon is adequate to stop variceal hemorrhage. It is quite effective as a bridge to more definitive therapy (TIPS or surgery) and cannot be

12 252 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER in place for more than 24 hours given the significant risk of esophageal necrosis and rupture. 167 Transjugular Intrahepatic Portosystemic Shunt (TIPS) TIPS involves placing a stent within the liver that bridges a branch of the intrahepatic hepatic vein with an intrahepatic branch of the portal vein, allowing diversion of blood flow away from the cirrhotic liver, decompressing portal pressures, and reducing the impetus to bleed. In experienced hands TIPS is a very effective method for stopping acute hemorrhage from esophageal varices but can be less effective in gastric variceal bleeding. 168 In the setting of variceal bleeding, TIPS should be reserved for cases that are refractory to endoscopic therapy, 169 orinthecaseofgastricvarices, used in conjunction with embolization. If recurrent bleeding occurs in a patient with a TIPS in place, the most important intervention is interrogation of the TIPS to document and treat thrombosis or stenosis. Until recently, TIPS was complicated by frequent stenosis and thrombosis. 168 Polytetrafluoroethylene (PTFE)-coated stents have significantly improved stent patency and the need for reintervention Although they have not been directly compared with surgical shunts, these data suggest they offer comparable results. Table 5 Precipitants of Hepatic Encephalopathy Infection Gastrointestinal bleeding Medical noncompliance Medication sedatives, narcotics, other Electrolyte disturbances Portosystemic shunting Transjugular intrahepatic portosystemic shunt Spontaneous Dehydration Excessive protein load Constipation Worsening liver function Surgery TIPS has significantly reduced the need for shunt surgery; however, surgery remains a good option in selected cases when TIPS is not technically feasible or fails or in patients with significant portal hypertension in the face of preserved hepatic synthetic function. The long-term patency rate of shunt surgery is thought to be superior to that of TIPS; however, newer coated stents may challenge this assumption Surgical alternatives for acute portal hypertensive hemorrhage include total or selective shunt surgery, devascularization procedures (Suguira or modification) or liver transplantation. If surgery is necessary, it is best done at a center with extensive experience. COMPLICATIONS ASSOCIATED WITH VARICEAL BLEEDING Hepatic Encephalopathy The initial approach to the patient with HE should focus on the identification and correction of any precipitant in addition to treatment of the encephalopathy. Common precipitants include gastrointestinal (GI) bleeding, medications, infection, dehydration, electrolyte disturbances, constipation, excessive protein load, portosystemic shunting (TIPS or spontaneous), and worsening liver function (Table 5). Potential precipitants such as these must be individually considered and subsequently excluded. In the case of infection, spontaneous bacterial peritonitis (SBP) is the most common infection in this population and must be ruled out with a diagnostic paracentesis as already discussed. Often, HE is the only manifestation of SBP. TREATMENT OF HEPATIC ENCEPHALOPATHY Nonabsorbable disaccharides and antibiotics have been shown to modify gut flora and decrease blood ammonia levels, but these are not necessarily related (indicating nonbacterial sources of ammonia, which may also be decreased by these compounds). Lactulose is the firstline therapy for HE. It is most effective if given orally and titrated to a dose that achieves three to four soft bowel movements a day. A common mistake in the ICU is continued lactulose despite diarrhea in the encephalopathic patient. Not only will this not improve encephalopathy, it may worsen it through free water depletion. If the patient is having adequate bowel movements on lactulose, but continues to be confused, several agents can be added. Nonabsorbable antibiotics such as neomycin or rifaxamin are effective for the treatment of HE either alone or in conjunction with lactulose. Metronidazole is also efficacious; however, side effects limit prolonged use. Zinc is a cofactor for the urea cycle and can increase the clearance of ammonia. Zinc levels are decreased in patients with cirrhosis and HE. Supplementation with zinc sulfate 600 mg/d normalizes zinc levels, decreases ammonia, and improves HE. 173 Branched-chain amino acids have not convincingly shown improvement in HE; however, they may be considered in patients that are not receiving protein in any form. 174,175 When HE is refractory to medical treatment other possibilities must be entertained. In those with a TIPS, occlusion or narrowing of the stent lumen can improve mental status. 176,177 If no TIPS or surgical shunt is present, abdominal imaging should be obtained

13 INTENSIVEMANAGEMENT OFHEPATICFAILURE/RINELLA, SANYAL 253 Table 6 Diagnostic Criteria for Hepatorenal Syndrome (International Ascites Club) MAJOR Chronic or acute liver disease with advanced hepatic failure and portal hypetension Creatinine> 1.5mg/dLor24-hourcreatinineclearance< 40mL/min Absence of shock, ongoing infection, use of nephrotoxic drugs, gastrointestinal or renal fluid losses > 500 g/d or > 1000 g/d in the setting of edema Urine protein < 500 mg/dl No ultrasonographic evidence of primary renal disease No sustained improvement in renal function after hydration MINOR Urine sodium < 10 meq/l Urine osmolality > plasma osmolality Urine red blood cells < 50 per high power field Urine output < 500 ml/d Serum sodium < 130 meq/l For the diagnosis of hepatorenal syndrome, all major criteria must be met. Minor criteria are supportive but not necessary for the diagnosis. to look for a prominent portosystemic collateral that could be radiographically embolized. 178 Infection Bacterial infections complicate 35 to 66% of cases of gastrointestinal bleeding in patients with AoCLF Not only is infection common after bleeding, it may also provoke rebleeding. 179 Furthermore, bacterial infection and the use of prophylactic antibiotics are independently associated with failure to control variceal hemorrhage in the first 5 days of admission. 180 Many randomized, controlled trials have shown that antibiotic prophylaxis targeted at enteric organisms (such as quinolones or third-generation cephalosporin) is effective in the prevention of postbleeding infection in cirrhotic patients. In addition, a meta-analysis of randomized, controlled trials concluded that antibiotic prophylaxis resulted in less infections and improved short-term survival in bleeding patients with cirrhosis. 185 Given these data, prophylactic systemic antibiotics should be given to cirrhotic patients with gastrointestinal hemorrhage. Spontaneous Bacterial Peritonitis SBP is a frequent and severe complication in those with cirrhosis and ascites. 186 It is associated with significant morbidity and mortality by precipitating renal failure in 30%, 187 worsening HE, and causing hemodynamic collapse in an already critically ill patient. The deterioration of renal function is the most sensitive predictor of inhospital mortality. 187,188 Renal failure often results from a reduction in effective circulating blood volume, cytokine surges, and activation of the renin-angiotensin system precipitated by infection. 187,188 Bacterial translocation from the gut is thought to be the most common mode of ascitic fluid inoculation. 189,190 Predisposing factors for the development of SBP include advanced liver disease, gastrointestinal bleeding, ascitic total protein fluid content 1 g/dl and a previous history of SBP. 181, INTERPRETATION OF A DIAGNOSTIC PERITONEAL TAP It is crucial to have a very low threshold to perform a diagnostic paracentesis in the patient with suspected SBP. Ideally, this should be done prior to the initiation of antibiotics. Peritoneal fluid should be sent for cell count, culture, albumin, total protein, LDH (lactate dehydrogenase) and glucose. Blood culture bottles should be inoculated at the bedside to improve yield. SBP is defined as an ascitic fluid polymorphonuclear (PMN) 250 cells/mm 3, in the setting of a positive monomicrobial ascitic fluid culture. 194,195 Culture positivity can fluctuate from one tap to the next; thus culture-negative neutrocytic ascites should be treated with antibiotics as previously outlined. 196 Monomicrobial non-neutrocytic bacterascites is another common variant of SBP. It is defined as a fluid cell count < 250 cells/ mm 3 with a positive culture. 197 Runyon and Hoefs and Chu et al found that 62 to 86% of cases of monomicrobial bacterial ascites resolve spontaneously, and those that did not resolve were symptomatic on presentation. 197,198 Thus, in a clinically stable asymptomatic patient, one could observe or consider repeat diagnostic paracentesis. However, in a critically ill patient with AoCLF in the ICU, antibiotic therapy may be the best course of action. TREATMENT OF SPONTANEOUS BACTERIAL PERITONITIS Patients should be given a non-nephrotoxic antibiotic with good enteric coverage such as a third-generation cephalosporin. Cefotaxime 2 g (q8h) is the beststudied antibiotic for the treatment of SBP. 199,200 Other antibiotics of comparable spectrum can be used and can be tailored if the organism is identified. Once the patient has been on antibiotics for 48 hours, 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 should be broadened. Once treatment efficacy is established, antibiotics should be given for 5 days. 201 Intravenous albumin is integral to the treatment of SBP has been shown in a randomized, controlled trial to decrease the incidence of renal failure and subsequent mortality when compared with antibiotics alone. 202 Based on these data, albumin should be given at a dose of 1.5 mg/kg on day 1 and 1 mg/kg on day 3. A recent study compared albumin to plasma expansion with hydroxyethyl starch. Fernandez and colleagues

14 254 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER found that only albumin improved hemodynamics in patients with SBP, suggesting that it may also have direct effects on the vascular endothelium. 203 Lifelong secondary antibiotic prophylaxis is mandatory in the patient with a history of SBP. Oral quinolones are most commonly used (norfloxacin); however, many antibiotics are effective for secondary prophylaxis of SBP. Table 6 illustrates the International Ascites Club classification of HRS. The pathophysiology of HRS is complex. Splanchnic arteriolar vasodilation leads to central vasodilation and compensatory activation of systemic and renal vasoconstrictor systems. 107,211 The resultant renal vasoconstriction leads to reduced glomerular filtration rate and increased water and sodium retention. ASCITES Ascitesistheresultofavidwaterandsodiumretention characteristic of the altered hemodynamics of cirrhosis and portal hypertension. It is associated with a 50% 2-year survival. Uncomplicated ascites is managed with sodium restriction (< 88 mmol/d) and diuretics; potassium sparing (i.e., spironolactone) alone, or in combination with a loop diuretic (i.e., furosemide). Diuretics are advanced until therapeutic efficacy is achieved or limited by worsening renal function or hyponatremia. In diuretic-refractory or resistant cases repeat large-volume paracentesis (LVP) with albumin infusion, TIPS, or peritonovenous shunts can be effective in improving the ascites but does not improve survival. 204,205 Ascites can be a difficult problem to manage in the ICU. Copious colloid and crystalloid infusion inevitably worsens ascites and diuretic use is often limited by hyponatremia, hypotension, or renal failure. Massive ascites can also alter respiratory mechanics and make breathing more labored or mechanical ventilation more challenging. Occasionally, massive ascites can worsen renal failure through compression of the renal arteries. LVP should be reserved for patient discomfort and improvement of respiratory mechanics when possible to avoid large-volume shifting and activation of vasoactive neurohumoral systems after paracentesis that can worsen renal perfusion. Such changes can be minimized with the use of albumin (6 to 8 g/l removed). Albumin administration helps maintain intravascular volume and minimize postparacentesis circulatory dysfunction. 205,206 RENAL FAILURE Twenty percent of cirrhotic patients with tense ascites develop renal failure characterized by the hepatorenal syndrome (HRS). 207,208 HRS is defined as functional renal impairment in a patient with advanced liver disease in the setting of normal tubular function and renal histology 209 (Table 6). Two types of HRS have been described; HRS I and HRS II, based upon the rapidity and extent of renal failure. 210 HRS I is characterized by a rapid and severe deterioration of renal function with survival measured in days to weeks, and HRS II represents a more indolent and stable renal dysfunction. Treatment of Hepatorenal Syndrome Liver transplantation is the ultimate treatment for HRS. After transplantation renal function returns to baseline in most cases. 212,213 Combination drug therapy that counteracts renal and systemic vasoconstriction leading to arterial hypotension and central hypovolemia with vasoconstrictors and plasma expanders, respectively, is the most effective strategy. Terlipressin, a long-acting vasopressin analogue that stimulates splanchnic V 1a vasopressin receptors increases blood pressure, GFR (glomerular filtration rate), and urine volume in patients with HRS. 214,215 Unfortunately, terlipressin is not yet available in the United States. In a small study of patients with HRS I, the combination of the a-agonist midodrine (7.5 mg tid), octreotide (100 g SQ tid), and albumin (25 g/day) was effective in improving renal function. 216 In a more recent study, these findings were confirmed and insertion of a TIPS in a subset of patients led to further improvement in renal function. 217 LIVER TRANSPLANTATION CHRONIC LIVER DISEASE Allocation of organs in chronic liver disease changed on February 27, The model of end-stage liver disease (MELD) system was adopted to objectify the way in which livers were allocated in the United States. It is a survival model based on a composite of three laboratory values: serum bilirubin, serum creatinine, and INR. The model was originally used to assess short-term mortality in cirrhotic patients undergoing elective TIPS placement. 218 This model was subsequently validated as an independent predictor of survival in patients with cirrhosis. 219,220 Thus priority on the liver transplant waiting list is based on the patient s blood group and the MELD score without emphasis on waiting time. SUMMARY Management of the patient with acute or chronic hepatic failure remains a challenging problem, despite advances in intensive care. Liver failure typically has profound effects on other organ systems and the effects of therapeutic interventions on other organs must be

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