Management of Pre-Liver Transplantation Patient-Part 2

CAQ CORNER Management of Pre–Liver Transplantation Patient— Part 2 Pratima Sharma1 and Jorge Rakela2

Liver transplantation (LT) has grown dramatically over blockade averages less than 50% and the maximum last 2 decades and the hepatologist has had to assume a benefit is seen in patients with Child-Turcotte-Pugh A larger role in managing the potential candidate awaiting and B cirrhosis. More than 30% of patients have no surgery. In part 1 of this review, we described the decrease in portal pressure despite adequate ␤ block- pre-LT evaluation process, contraindications of LT, ade.10 The addition of long-acting nitrates to nonselec- general care, and treatment of various etiologies of liver tive ␤-blockers has been shown to enhance their hemo- disease prior to LT. In this part, we review the manage- dynamic effect and reduce the risk of bleeding from ment of liver-specific complications that are responsible esophageal varices and therefore should be considered for significant morbidity and waitlist mortality of LT in patients who do not respond ideally to ␤-blockers.11 candidates. Poorer results compared with pharmacotherapy have led to the discontinuation of endoscopic variceal sclerotherapy as primary prophylaxis for variceal bleed- Liver-Specific Complications ing.12–14 Sarin et al.15 showed that endoscopic variceal Portal Hypertension band ligation is safer and more effective than propranolol for the primary prevention of variceal bleeding. Portal hypertension is the main complication of liver However, in a recent randomized controlled multi- cirrhosis. This syndrome develops in the majority of center trial that evaluated primary prophylaxis of patients with cirrhosis and is responsible for most life- variceal bleeding, variceal band ligation and proprano- threatening complications of cirrhosis, including gas- 16 trointestinal bleeding from ruptured gastroesophageal lol were similarly effective. Despite effectiveness in varices, hepatorenal syndrome, and hepatic encepha- the arrest of bleeding, TIPS cannot be recommended as lopathy. a 1st-line approach to manage variceal bleeding or for primary prophylaxis because of increase incidence of Prophylaxis of Esophageal Variceal Bleeding hepatic encephalopathy and expense related to the The average lifetime risk of variceal bleeding in patients management of TIPS malfunction.17,18 with cirrhosis who have had no previous bleeding is Gastric Variceal Bleeding 30%.1 Each bleeding episode bears a mortality risk of 30 to 50%.2 In prospective studies, advanced Child- No specific measures are available to prevent 1st bleed- Turcotte-Pugh stage, large esophageal varices, and red ing from gastric varices. Most of the current regimens to wale markings are independent risk factors for 1st treat gastric varices are derived from anecdotal evidence variceal bleed.3–5 The modalities available for primary prophylaxis are nonselective ␤-blockers, endoscopic Abbreviations: LT, liver transplantation; HRS, hepatorenal syn- therapy, and transjugular intrahepatic portosystemic ␤ drome; HPS, hepatopulmonary syndrome; HE, hepatic encephalop- shunt (TIPS). Nonselective -blockers decrease portal athy; PPH, portopulmonary hypertension; SBP, spontaneous bacte- pressure and collateral flow through a combination rial peritonitis; PAP, pulmonary artery pressure; TIPS, transjugular of decreased cardiac output and unopposed alpha- intrahepatic portosystemic shunt. 1 mediated splanchnic vasoconstriction, resulting in From the Department of Medicine, Emory University Hospital, Atlanta, GA, and the 2Department of Internal Medicine, Mayo Clinic, decreased effective splanchnic blood flow, thereby Scottsdale, AZ. reducing the risk of initial variceal bleeding and a trend Address reprint requests to Pratima Sharma, MD, Assistant Profes- toward decreased mortality.6–8 ␤-blockers should be sor, Emory University Hospital, 1364, Clifton Road, Box 7, Atlanta, GA considered in all patients with large varices and red 30322. Telephone: 404 712 5454; FAX: 404 712 4621; E-mail: markings.7 Propranolol or nadolol can be used and the [email protected] Copyright © 2005 by the American Association for the Study of dose should be titrated weekly to decrease the resting Liver Diseases heart rate by 25% and the systolic blood pressure to no Published online in Wiley InterScience (www.interscience.wiley.com). lower than 90 mm of Hg.9 The risk reduction with ␤ DOI 10.1002/lt.20379

Liver Transplantation, Vol 11, No 3 (March), 2005: pp 249–260 249 250 Sharma and Rakela or are extrapolated from trials of esophageal varices.14,19 terlipressin for controlling bleeding. The side effects TIPS is very effective with a success rate of 90% for were less frequent and less severe with octreotide than initial hemostasis. The rate of early rebleeding after with either vasopressin or terlipressin. However, the TIPS procedure is 20% and often the source of such efficacy of octreotide as a single therapy is controversial. bleeding is nonvariceal, i.e., ulcer secondary to banding Results from a recent meta-analysis suggest that oct- or sclerosis.18 reotide may improve the results of endoscopic therapy but has no or little effect if used alone.19 Treatment of Acute Variceal Bleeding Endoscopic sclerotherapy controls active hemor- Patients suspected of acute variceal bleeding should be rhage in 80 to 90% of patients. However, a skilled managed in the intensive care setting. General princi- endoscopist must be readily available, and the proce- ples of resuscitation should be followed, which include dure is associated with serious complications in 10 to protection of airway, insertion of 2 large-bore intrave- 20% of patients, with an overall mortality of 2%.19 The nous cannulas, blood volume resuscitation with packed combination of sclerotherapy with somatostatin, oct- erythrocytes, correction of coagulopathy with fresh fro- reotide, and vapreotide has been reported to be superior zen plasma, and platelet transfusion if they are below to sclerotherapy alone in terms of control of bleeding 23,24 30,000/mm3. Care must be taken not to overexpand and reduction of treatment failures within 5 days. plasma volume, which may increase portal pressure and The 6-week survival of the combination of sclerother- result in exacerbation of variceal bleeding and ascites. apy and drugs was similar to sclerotherapy alone. Antibiotics should be administered prophylactically, Variceal band ligation was shown to be better than especially in patients with ascites, to prevent spontane- endoscopic sclerotherapy in controlling the acute bleed and mortality.25 The banding may be more challenging ous bacterial peritonitis.20,21 Emergency endoscopy of during active bleeding due to reduction in the field of the upper gastrointestinal tract can then be performed vision by as much as 30% with the addition of banding and the most appropriate treatment modality should be device to the endoscope. The choice of procedure chosen at that point. The drug classes that have been depends on the available expertise in the center manag- extensively studied in acute variceal bleeding are vaso- ing the patient; variceal banding has become the proce- pressin and somatostatin and their analogs. Both soma- dure of choice in the management of variceal bleeding. tostatin and vasopressin arrest variceal bleeding by caus- Balloon tamponade is a useful temporary measure to ing splanchnic vasoconstriction and thereby decreasing control acute variceal bleeding and to stabilize the the portal pressure, but this has no effect on mortality.19 patient while more definitive procedures are being There is an increased association between myocardial accomplished. Control of bleeding is successful in as infarction and arrhythmias and the use of vasopressin. many as 80 to 90% of cases, but rebleeding occurs in up Furthermore, bowel ischemia, cerebrovascular isch- to 50% when the balloon(s) are deflated. Furthermore, emia, and peripheral tissue necrosis have been reported. significant perforation risk is present that may lead to The severity of complications such as myocardial isch- high mortality if the balloons are inflated for prolonged emia has led to discontinuation of the use of vasopres- periods of time.7 14 sin. Rebleeding is a very common and usually occurs Terlipressin is a longer acting analog of vasopressin within 6 weeks of the index episode. The recurrence and can be given as bolus-infusion every 4 hours. Its reported as high as 70% in patients who have had at efficacy is similar to vasopressin in controlling the acute least 1 prior bleeding episode.21 The use of ␤-blockers variceal bleeding and is associated with fewer side (with and without variceal band ligation) is the most effects.22 The ease of administration has allowed for accepted approach to manage these patients. There is paramedic administration in the field with arrest of still debate about the cost-effectiveness of this pharma- bleeding prior to arrival at the hospital. Terlipressin is cological approach combined with endoscopy. not yet approved for use in the United States. In approximately 10% of patients in whom rebleed- Somatostatin is superior to vasopressin for immedi- ing cannot be controlled with 2 endoscopic therapeutic ate control of bleeding and has less severe side effects sessions within 24 hours, either surgery or TIPS should than vasopressin, although survival improvement has be planned. At the most recent American Association not been seen with somatostatin.19 for the Study of Liver Diseases meeting, Henderson et Octreotide is a synthetic analog of somatostatin. al.26 presented the 1st analysis of the multicenter study When compared with other vasoactive drugs, oct- of distal splenorenal shunt vs. TIPS for refractory reotide was better than vasopressin and equivalent to variceal bleeding. This study found that both modali- Pre–LT Patient Management—Part 2 251 ties were equally effective in preventing rebleeding, and maximum of 400 mg/day / 160mg/day, if weight loss encephalopathy and survival were similar. TIPS can be and natriuresis are inadequate on lower doses. In gen- used in patients with Child-Turcotte-Pugh class B or C eral, this ratio maintains normokalemia. Furosemide cirrhosis as a salvage therapy and preferably as a bridge can be temporarily withheld in patients presenting with to transplant.18 Worsening of hepatic encephalopathy hypokalemia. Single morning dosing tends to increase after TIPS procedure may impair the outcome com- compliance and is recommended. The antiandrogenic pared to Child-Turcotte-Pugh A patients. effects of spironolactone, such as decreased libido, impotence, and gynecomastia in men may require dose Ascites reduction or discontinuation of the medicine. Amilo- Ascites is the most common major complication of ride can be substituted for spironolactone, but it is more portal hypertension. The initial evaluation of a patient expensive and has been shown to be less effective in a with ascites should include a history, physical evalua- randomized control trial. tion, and abdominal paracentesis with ascitic fluid anal- The etiology of nocturnal muscle cramps is not well ysis. Bleeding is sufficiently uncommon so as to obviate understood and may respond to magnesium supple- the routine requirement for fresh frozen plasma or mentation or the oral administration of quinine sulfate platelets prior to a diagnostic paracentesis.27 The initial at a dose of 325 mg in the evening. Serum sodium less ascitic fluid analysis should include a cell count and than 120 mmol/day despite fluid restriction and serum Ͼ differential and serum-ascites albumin gradient. The creatinine 2.0 mg/dL should result in the cessation of culture yield increases to 80% when ascitic fluid with a diuretic therapy, reassessment of the situation and con- polymorphonuclear count Ͼ250 cells/mm3 is inocu- sideration of 2nd-line options. These patients should be monitored for daily weight, orthostatic symptoms, and lated directly into blood culture bottles at the bed- periodic serum electrolytes, blood urea nitrogen, and side.5,28,29 creatinine. Random urine sodium concentration is The mainstay of treatment of patients with ascites measured if the weight loss is not adequate. The fre- includes education regarding dietary sodium restriction quency of follow-up is determined by response to treat- (2,000 mg/day or 88 mmol/day) and oral diuretic ther- ment and by patient stability. apy30 that has been shown to be effective in 90% of Refractory ascites is defined as ascites that is not patients.31 Chronic hyponatremia is commonly seen in responsive to sodium-restricted diet and high-dose cirrhotic patients and is seldom morbid, although diuretic treatment in the absence of prostaglandin recent data has shown that hyponatremia is an indepen- inhibitors such as nonsteroidal antiinflammatory 32 dent risk factor for death while awaiting LT. Rapid drugs.30,36 Serial therapeutic paracentesis are effective attempts to correct hyponatremia can lead to more in controlling ascites. Serial therapeutic paracentesis complications, such as central pontine myelinolysis, should be performed as needed, approximately every 2 than hyponatremia itself, although severe hyponatre- weeks. The postparacentesis albumin infusion is expen- mia will increase the risk of posttransplant neurological sive and unproven to be necessary for paracentesis of 33 complications. Severe hyponatremia (serum sodium Ͻ5 L. For larger volume paracentesis, an albumin infu- Ͻ 120 mmol/L) requires fluid restriction in cirrhotic sion of 5–8 g/L of ascitic fluid removed can be consid- patients with ascites. Cirrhotic patients do not usually ered.30 have symptoms from hyponatremia until their sodium LeVeen or Denver shunts were popularized in the levels fall below 110 mmol/L, or unless the decline in 1970s as a physiologic treatment of ascites. Shunt place- sodium is very rapid. Recently, Gerbes et al.,34 showed ment has been shown in controlled trials to decrease the that VPA-985, an orally active vasopressin 2 receptor duration of hospitalization, the number of hospitaliza- antagonist, can correct severe hyponatremia in patients tions and the dose of diuretics.37,38 However, their poor with cirrhosis and ascites,34 its clinical utility remains to long-term patency, significant complication profile, be determined and lack of survival advantage compared with medical The usual diuretic therapy consists of single morn- therapy in controlled trials have led to near abandon- ing doses of oral spironolactone and furosemide, begin- ment of these devices.38 Shunt-related fibrous adhe- ning with 100 and 40 mg, respectively.30 Single-agent sions can make subsequent LT difficult.39 furosemide has been shown to be less efficacious than TIPS is physiologically equivalent to a side-to-side spironolactone in a randomized controlled trial.35 The portocaval shunt that is placed by an interventional dose of both oral diuretics can be increased simulta- radiologist.40 Five randomized trials41–45 comparing neously, maintaining the 100 mg / 40 mg ratio, with a TIPS and large volume paracentesis have demonstrated 252 Sharma and Rakela that TIPS is effective in minimizing ascites and in symptoms of infection should also receive empiric anti- reducing the need for paracentesis. However, whether biotic therapy.30,46 the TIPS procedure improved survival of the patients Oral ofloxacin has been reported in a randomized with cirrhosis and refractory ascites is still debated; the controlled trial to be as effective as parenteral cefo- trials have reported the discordant results of the effect of taxime in the treatment of SBP in patients who are not TIPS on survival. Rossle et al.42 and Salerno et al.43 vomiting and are not in shock.49 Repeat paracentesis showed that TIPS was independently associated sur- should be performed to document cultures sterility and vival without LT. Salerno et al.43 observed the relative decrease in polymorphonuclear cell count in patients risk of dying was 2.95 times greater in patients assigned with SBP; this step is particularly important in cases in to the paracentesis group, according to the multivariate which clinical improvement is not apparent after the 1st analysis. The results from the North American Study 3 days of antibiotic therapy.50 for the Treatment of Refractory Ascites41 and a ran- Short-term inpatient quinolone should be consid- domized trial from the University of Barcelona, Spain44 ered in the prevention of bacterial infections in patients Ͻ showed that TIPS is substantially superior to conven- with low protein ( 1 gm/dL) ascites, variceal hemor- tional medical therapy but does not improve the sur- rhage, and prior SBP. Long-term outpatient antibiotic vival or quality of life. The reasons why randomized use can probably be reserved for patients who have 30,50 trials have not demonstrated a survival benefit are survived an SBP infection. unclear. However, the Child-Turcotte-Pugh class or its Hepatic Encephalopathy component was similar among the trials. Factors associated with increased mortality after TIPS include Hepatic encephalopathy (HE) is a complex neuropsy- Child-Turcotte-Pugh class C, renal insufficiency, chiatric syndrome that may complicate acute or chronic liver failure. It is characterized by changes in mental hyperbilirubinemia, marked coagulopathy, and state, including a wide range of neuropsychiatric symp- advanced age.45 Before recommending TIPS to LT can- toms ranging from minor signs of altered brain function didates, the risks and benefits should be carefully to deep coma. assessed to avoid a potentially catastrophic outcome. Most theories explaining the pathogenesis of HE Spontaneous Bacterial Peritonitis accept that nitrogenous substances derived from the gut adversely affect brain function. These compounds gain Spontaneous bacterial peritonitis (SBP) is a particularly access to the systemic circulation as a result of decreased important complication because the presence of infec- hepatic function or portosystemic shunts and may pro- tion usually removes a patient from consideration of duce alterations of neurotransmission that affect con- transplantation until the infection is cleared. A diagnos- sciousness and behavior.51 Abnormalities in glutamin- tic abdominal paracentesis must be performed and the ergic, serotoninergic and gamma-aminobutyric ascitic fluid must be analyzed for cell count and bacte- acidergic, and catecholamine pathways, among others, rial culture before a confident diagnosis of ascitic fluid have been described in experimental HE.51 A large body infection is made. The diagnosis of SBP is made when of work points towards ammonia as a key factor in the Ͼ there are 250 polymorphonuclear cells per milliliter pathogenesis of HE.52 and / or positive ascitic fluid bacterial culture without The approach to HE has not changed significantly an evident intraabdominal or surgically correctable in recent years. HE is a diagnosis of exclusion and is source.46 These patients should receive empiric treat- mainly clinical. The suspicion of HE in patients with ment with broad-spectrum antibiotics. Delaying treat- chronic liver disease should prompt the search for the ment until the ascitic fluid culture grows bacteria may precipitating factors that include gastrointestinal bleed- result in the patients’ death from overwhelming infec- ing, electrolyte abnormalities, renal failure, infection, tion. Cefotaxime, a 3rd generation cephalosporin, has recent placement of TIPS shunt,53 use of sedatives / been shown to be superior to ampicillin in combination hypnotics, development of hepatocellular carcinoma, with tobramycin in a controlled trial.47 In a randomized and constipation. However, the other causes of change controlled trial involving 100 patients, it has been in mental status such as intracranial bleed or masses, reported that 5 days of treatment is as efficacious as 10 hypoglycemia, and a postictal state should be ruled out. days of treatment in the treatment of carefully charac- Although hyperammonemia is associated with HE, terized patients with SBP.48 Patients with less than 250 ammonia levels do not correlate with the level of polymorphonuclear cells in ascitic fluid and signs or encephalopathy.54 Pre–LT Patient Management—Part 2 253

The treatment goals for HE are provision of sup- liver. Strategies to stimulate residual urea cycle activities portive care, identification and removal of precipitating and / or glutamine synthesis have been tried over the factors, and reducing the production and absorption of last 20 years. One of the most successful agents to be nitrogenous load from the gut. Ultimately, assessment used so far is L-ornithine L-aspartate. Randomized con- of the need for long-term therapy is very important. trolled clinical trials with L-ornithine L-aspartate dem- There is no good clinical evidence supporting pro- onstrate significant ammonia lowering and concomi- tein restriction in patients with acute hepatic encepha- tant improvement in psychometric testing.60 lopathy. The only randomized trial, reported only in Benzoate is also effective in reducing blood ammo- abstract form, found no difference between moderate nia both in patients with inherited urea cycle disorders (.8 gm/kg per day) and more aggressive protein restric- and in cirrhotic patients. In a randomized controlled tion.51 Zinc, a cofactor of urea cycle enzymes, may be clinical trial with sodium benzoate vs. lactulose, deficient in cirrhotic patients, especially if associated improvement in neuropsychiatric performance was with malnutrition. Zinc supplementation improves the found to be comparable.61 activity of the urea cycle in experimental models of Several controlled clinical trials have been per- 55 cirrhosis. One trial has evaluated the effects of zinc formed to assess the efficacy of the benzodiazepine over a short period (up to a week), without major receptor antagonist flumazenil in cirrhotic patients with improvement. Another nonrandomized study reported various degree of severity of HE.62 Spectacular positive results with administration of zinc for 3 improvements in neuropsychiatric status were recorded 56,57 months. However, this anecdotal report has not in a subset of patients receiving flumazenil. However, been confirmed in larger studies. the possible confounding effects of prior exposure to Nonabsorbable disaccharides such as lactulose are benzodiazepines, possibility of seizures, and lack of cor- routinely used to decrease ammonia production in the relation between the clinical response and blood levels gut. Lactulose increases fecal nitrogen excretion by of diazepines have tempered enthusiasm for the use of facilitation of the incorporation of ammonia into bac- benzodiazepine receptor agonist in these patients.63 teria as well as by its cathartic effect.51 Lactulose administered orally reaches the cecum, where it is metabolized Renal Insufficiency and Hepatorenal Syndrome by the enteric bacteria, causing a fall in pH. This drop in Acute renal failure is thought to be common in patients pH leads to metabolic shift in bacteria favoring uptake with cirrhosis, but its exact incidence is variable. of ammonia.58 The dose is adjusted to produce 2 or 3 Patients with cirrhosis are predisposed to acute renal soft bowel movements daily.51 A systematic review found that lactulose or lactitol were more effective than failure following complications such as variceal bleed- placebo in improving hepatic encephalopathy but had ing or administration of nephrotoxic drugs such as non- no significant benefit on mortality.59 However, the steroidal antiinflammatory drugs, antibiotics, dilti- benefit on encephalopathy no longer reached statistical azem, etc. The cause of renal insufficiency could be significance when the analysis was confined to studies prerenal, intrarenal, or hepatorenal. The management with the highest methodologic quality. The authors of renal insufficiency in patients awaiting LT focuses on also found that antibiotics appeared to be relatively prevention of additional injury and optimization of more effective. existing renal function. Nonsteroidal antiinflammatory Antibiotics such as neomycin, low dose metronida- drugs should be used only with close follow-up, because zole, vancomycin, and rifaximin are also useful for low- the subsequent decrease in renal prostaglandin may pre- ering blood ammonia, mainly by an effect on ammonia cipitate acute renal failure. Radiographic imaging stud- production by intestinal bacteria. However, antibiotic ies using intravenous contrast dye also need to be therapy may be associated with significant toxic side approached with caution because of the known risk of effects (e.g., renal failure, ototoxicity, and peripheral renal injury. The use of acetylcysteine together with neuropathy). hydration is the treatment of choice to protect against An alternate strategy for lowering of blood ammonia radiographic contrast media–induced nephropathy.64 is the stimulation of ammonia fixation. Under normal Large volume paracentesis followed by intravenous physiological conditions, ammonia is removed by the albumin infusion decreases the risk of acute renal failure formation of urea in periportal hepatocytes and by glu- after paracentesis.30 The results of albumin use in this tamine synthesis in perivenous hepatocytes, skeletal clinical setting are better than other volume expanders muscle, and brain. In cirrhosis, both urea cycle enzymes such as dextran.65,66 In a recent study comparing nor- and glutamine synthetase activity are decreased in the mal saline and albumin, albumin was more effective 254 Sharma and Rakela than saline in the prevention of paracentesis-induced recirculating system combined with intermittent circulatory dysfunction.67 Saline is a valid alternative to venovenous hemofiltration vs. intermittent veno- albumin when less than5Lofascitic fluid is evacuated. venous hemofiltration alone, suggests that the molec- Moreover, patients with cirrhosis may develop a spe- ular adsorbent recirculating system may improve sur- cific acute renal failure called hepatorenal syndrome vival in HRS.75 (HRS). It is a diagnosis of exclusion. HRS is an omi- nous complication of end-stage liver disease. Retrospec- Hepatopulmonary Syndrome ϳ tive studies indicate that HRS is present in 17% of Hepatopulmonary syndrome (HPS) is a progressive, patients admitted to the hospital with ascites and in debilitating complication of end-stage liver disease that Ͼ 50% of cirrhotic patients who die from liver failure. occurs in 4 to 25% of liver transplant candidates.76–78 The hallmarks of HRS are reversible renal constriction The diagnosis of HPS rests on the triad of cirrhosis, and mild systemic hypotension.68 The kidneys are hypoxemia, and intrapulmonary vascular dilation. Pul- structurally normal and at least in the early part of the monary features include digital clubbing, cyanosis, dys- syndrome, tubular function is intact, as reflected by pnea, platypnea, and orthodeoxia. avid sodium retention and oliguria. The cause of renal Ͻ LT candidates with hypoxemia (PaO2 70 mm of vasoconstriction is unknown, but its pathogenesis may Ͼ predominantly involve both increased vasoconstrictor Hg or arteriolar–aveolar gradient 20) in the absence and decreased vasodilator factors. Two patterns of HRS of any pulmonary dysfunction, should be screened for are observed in clinical practice: type 1 and type 2. Type HPS since the syndrome appears to resolve after ortho- 1 HRS is an acute form of HRS in severe liver disease topic LT. Further work-up should include an arterial and is progressive. It is associated with poor prognosis blood gas on 100% oxygen, double contrast echo or with 80% mortality at 2 weeks. Type 2 HRS occurs in 99mTC macro-aggregated albumin lung perfusion patients with diuretic-resistant ascites. The course of scan to establish the presence of intrapulmonary vascu- renal failure is slow. It is also associated with poor prog- lar dilatation. The presence of microbubbles in the left nosis, although the survival time is longer than that of cardiac chambers between 3 and 6 heartbeats after the patients with type 1 HRS. The definition of HRS was visualization in the right chambers and a shunt fraction proposed by the International Ascites Club.36 of more than 6% is considered as a positive test for the Although the best treatment for HRS is LT, presence of intrapulmonary vascular dilatation and thus patients with HRS who are transplanted have more confirms the diagnosis.79,80 Figure 1 illustrates the work complications and a higher in-hospital mortality rate for HPS. than those without HRS.69 It has been suggested that Patients with HPS awaiting LT get a priority over systemic vasoconstrictor therapy may improve renal other patients. Complete resolution after orthotopic function in patients with HRS by increasing the LT even in the setting of severe hypoxemia has been effective arterial blood volume. A nonrandomized 59,77 well documented. However, PaO2 less than 50 mm retrospective study in a large series of patients with of Hg and 99mTC macro-aggregated albumin brain HRS suggests that the vasopressin analog terlipressin uptake Ͼ20% are the pretransplantation risk factors for is an effective treatment of renal failure.70 Other increased mortality. nonrandomized studies suggest that vasoconstrictive Efforts have to be made to rule out intrapulmonic therapy with noradrenaline71 or midodrine com- shunting. Pharmacologic approaches have been disap- bined with octreotide72 may improve renal function pointing in providing consistent and reproducible in these patients. TIPS has previously been shown to improvement in hypoxemia.81 The placement of TIPS have beneficial effect on renal function in HRS.73 In a recent study by Wong et al.,74 TIPS was associated to improve hypoxemia due to HPS remains controver- with further improvement in the renal function as sial and cannot be advised without further prospective 82 well as circulatory function, with normalization of study. Coil embolization to occlude discrete arterio- effective arterial blood volume in selected type 1 venous communications in patients with severe hypox- HRS patients (international normalized ratio less emia and HPS has resulted in significant improvement 83 than 2, bilirubin less than 5 mg/dL, and Child-Tur- in PaO2 in 2 adults. Embolotherapy is an accepted cotte-Pugh lower than 12), following administration approach to the management of severe hypoxemia asso- of combination therapy with midodrine, octreotide, ciated with discrete arteriovenous malformation,84 but and albumin.74 A randomized study in a small series is not effective in HPS due to capillary dilation without of patients, comparing the molecular adsorbent discrete anatomic shunting. Pre–LT Patient Management—Part 2 255

epoprostenol (prostacyclin, or prostaglandin I2)isa potent vasodilator shown to improve exercise tolerance, reduce pulmonary vascular resistance, and improve mortality in patients with primary pulmonary hypertension.87 Similar hemodynamic improvements have been achieved before LT in patients with PPH.88,89 Kuo et al.88 treated 4 patients with 10–28 ng/kg/minute of epoprostenol over 6 to 14 months and reported a 29 to 46% decrease in mean PAP, a 22 to 71% decrease in pulmonary vascular resistance, and a 25 to 75% increase in cardiac output. Krowka et al.89 treated 10 patients with mean PAP of 35 mm of Hg and higher for 8 days to 30 months. Six patients showing improvements in pulmonary vascular resistance, mean PAP, and cardiac output after 1 hour had further reduction of pulmonary vascular resistance when treated with continuous therapy. Not enough data exist regarding the long term benefit of epoprostenol therapy or regarding the lasting effect after the cessation of therapy to make any recommendations. However, epoprostenol therapy is most appropriate for the cirrhotic patient who except for moderate to severe PPH has no other contraindica- tion for LT. Figure 1. Work-up for hepatopulmonary syndrome. Hepatic Hydrothorax Hepatic hydrothorax is defined as the accumulation of Portopulmonary Hypertension fluid in the pleural space as a consequence of liver disease. The most common symptom is dyspnea without Portopulmonary hypertension (PPH) refers to the chest pain. It can be detected with chest radiographs in development of pulmonary arterial hypertension in the as many as 13% of patients with cirrhosis. Right-sided setting of portal hypertension with or without liver disease. It is defined as mean pulmonary artery pressure pleural effusion is seen in 66% of the patients with 90 (PAP) Ͼ25, with a normal pulmonary capillary wedge hepatic hydrothorax. The management options for pressure, an elevated pulmonary vascular resistance hepatic hydrothorax include medical management of Ͼ125 dynes/second/cm–5, or increased trans pulmo- ascites, and therapeutic thoracocentesis for the control nary gradient (mean PAP / pulmonary capillary wedge of shortness of breath. The pleural fluid usually has the pressure Ͼ10 mm of Hg).85 Candidates with PAP characteristics of a transudate. However, an occasional greater than or equal to 40 mm of Hg on echocardiog- patient with hepatic hydrothorax may develop “spon- raphy should undergo a right heart catheterization to taneous bacterial pleuritis.” They should be treated as confirm the diagnosis of PPH. Figure 2 illustrates the for SBP; insertion of chest tube is contraindicated in work-up for PPH. It has been estimated that in patients these patients. TIPS has been successfully used to man- who undergo LT with a mean PAP between 35 and 49 age the symptoms of hepatic hydrothorax in the setting mm of Hg and pulmonary vascular resistance Ͼ250 of marked ascites.91 Pleurodesis of the pleural space dynes/second/cm–5 or greater, the mortality is 50%. with chemical means such as talc, antibiotics, or che- Patients with a mean PAP of 50 mm of Hg or greater motherapeutic agents usually fails. Video thoracoscopy have a cardiopulmonary mortality rate of 100%.86 It is with the repair of presumed diaphragmatic defects has therefore recommended that moderate to severe PPH been described in the literature.92 and significant right ventricle dysfunction should be Pruritus considered contraindications to LT. However, preoperative therapy to reduce PPH and Pruritus is a common symptom of chronic cholestatic right ventricular dysfunction may improve clinical sta- liver diseases, particularly primary biliary cirrhosis. The tus and make LT feasible. Continuous intravenous 1st line of treatment is cholestyramine, an anion 256 Sharma and Rakela

Figure 2. Work-up for portopulmonary hypertension. PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; PGI2, prostaglandin I2; ECHO, echocardiogram; RHC, right heart catheterization. exchange resin. It should be administered at least 4 ness of opioid receptor antagonists (nalmefene, nalox- hours before or after taking the other medications, as it one, and naltrexone) in the control of pruritus.95,96 The binds many drugs.93 Side effects include bloating, con- major side effects are the symptoms of opioid with- stipation, and sometimes diarrhea. The 2nd line of drawal. The treatment should be started slowly, prefer- medication is rifampin.94 The mechanism of action is ably in a hospital setting. unclear but it is effective in controlling pruritus in 50% of the patients with primary biliary cirrhosis. Dosage is Management of Osteopenia and Osteoporosis 150 mg twice a day and it is effective within 6 weeks of therapy. The drug should be taken regularly for the Osteoporosis and fractures are more common in cir- effectiveness of treatment. These patients should be rhotic patients than in the general population in the monitored closely for the possibility of drug hepatotox- absence of confounding risk factors such as female gen- icity. Several studies have demonstrated the effective- der, cholestasis, and excess alcohol intake.97,98 The role Pre–LT Patient Management—Part 2 257 of calcium and vitamin D in preventing osteoporosis is esophageal endoscopy. Gastrointest Endosc 1981;27:213– unclear. According to recently published guidelines on 218. the management of osteoporosis associated with 4. D’Amico G, Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding. Baillieres Clin chronic liver disease, patients with cirrhosis or severe Gastroenterol 1997;11:243–256. cholestasis should have a baseline bone mineral densi- 5. Runyon BA, Canawati HN, Akriviadis EA. Optimization of tometry.99 If the T score is more than –1.5 or between ascitic fluid culture technique. Gastroenterology 1988;95: –1.5 and –2.5, no treatment is recommended. These 1351–1355. patients should be followed up with bone mineral den- 6. Riggio O, Ariosto F, Merli M, Caschera M, Zullo A, Balducci G, et al. Short-term oral zinc supplementation does not sitometry every 2 years.100 The work-up for the patients improve chronic hepatic encephalopathy. Results of a double- with bone mineral densitometry less than –2.5 should blind crossover trial. Dig Dis Sci 1991;36:1204–1208. include thyroid function tests, serum calcium, phos- 7. Vargas HE, Gerber D, Abu-Elmagd K. Management of portal phate, estradiol, follicle stimulating hormone, luteiniz- hypertension-related bleeding. Surg Clin North Am 1999;79: ing hormone, testosterone, and sex hormone binding 1–22. globulin levels. The optimum duration of therapy has 8. Feu F, Bordas JM, Luca A, Garcia-Pagan JC, Escorsell A, Bosch 100 J, Rodes J. Reduction of variceal pressure by propranolol: com- not been established. parison of the effects on portal pressure and azygos blood flow The current recommendation is that the treatment in patients with cirrhosis. Hepatology 1993;18:1082–1089. should be given for a minimum of 5 years and the bone 9. Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, mineral densitometry repeated after 2 years and at the Lebrec D. Beta-adrenergic-antagonist drugs in the prevention end of treatment.100 In women, hormone replacement of gastrointestinal bleeding in patients with cirrhosis and esoph- therapy with estrogen and progesterone should be ageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian offered to premenopausal females. For men, transder- Multicenter Study Group. N Engl J Med 1991;324:1532– mal testosterone can be given to hypogonadal males. 1538. The treatment recommendation for patients unable 10. Garcia-Tsao G, Grace ND, Groszmann RJ, Conn HO, Ber- to take hormone replacement therapy / testosterone or mann MM, Patrick MJ, et al. Short-term effects of propranolol eugonadal is bisphosphonates. Calcitriol or calcitonin on portal venous pressure. Hepatology 1986;6:101–106. should be considered in those patients with osteoporo- 11. Garcia-Pagan JC, Feu F, Bosch J, Rodes J. Propranolol compared with propranolol plus isosorbide-5-mononitrate for por- sis who are either intolerant of hormone replacement tal hypertension in cirrhosis. A randomized controlled study. therapy and bisphosphonates or whose bone mineral Ann Intern Med 1991;114:869–873. densitometry worsens despite either the use of bisphos- 12. Fardy JM, Laupacis A. A meta-analysis of prophylactic endo- phonates or treatment of hypogonadism. scopic sclerotherapy for esophageal varices. Am J Gastroenterol In the absence of larger studies on the effect of vita- 1994;89:1938–1948. min D supplementation on bone mineral densitometry, 13. Paquet KJ, Kalk JF, Klein CP, Gad HA. Prophylactic sclerotherapy for esophageal varices in high-risk cirrhotic patients it seems reasonable to recommend correction of vita- selected by endoscopic and hemodynamic criteria: a random- min D deficiency with an oral daily dose of 800 IU of ized, single-center controlled trial. Endoscopy 1994;26:734– vitamin D, and 1–2 gm of elemental calcium supple- 740. mentation. 14. D’Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995;22:332– 354. Conclusion 15. Sarin SK, Lamba GS, Kumar M, Misra A, Murthy NS. Com- parison of endoscopic ligation and propranolol for the primary The care and monitoring of pre-LT candidates is very prevention of variceal bleeding. N Engl J Med 1999;340:988– challenging. 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