Management of gastrointestinal bleeding in patients with cirrhosis

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Management of gastrointestinal bleeding in the cirrhotic patient Audrey E. Ertel MD, MS, Alex L. Chang MD, Young Kim MD, MS, Shimul A. Shah MD, MHCM, FACS

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Cite this article as: Audrey E. Ertel MD, MS, Alex L. Chang MD, Young Kim MD, MS, Shimul A. Shah MD, MHCM, FACS, Management of gastrointestinal bleeding in the cirrhotic patient, Current Problems in Surgery, http://dx.doi.org/ 10.1067/j.cpsurg.2016.06.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Management of Gastrointestinal Bleeding in the Cirrhotic Patient

Audrey E. Ertel MD, MSa, Alex L. Chang MDa, Young Kim MD, MSa, Shimul A. Shah MD, MHCM, FACSa Cincinnati Research in Outcomes and Safety in Surgery (CROSS) aDepartment

of Surgery, University of Cincinnati School of Medicine

Cincinnati, OH

Grants and Financial Support Funding was from the University of Cincinnati Department of Surgery

Corresponding Author: Shimul A. Shah, MD, MHCM Associate Professor of Surgery Division of Transplantation University of Cincinnati School of Medicine 231 Albert Sabin Way, ML 0558, MSB 2006C Cincinnati, OH 45267-0558 Phone: 513-558-3993 Fax: 513-558-8689 Email: [email protected]

Abbreviations · BATO: balloon-occluded antegrade transvenous obliteration · BRTO: balloon-occluded retrograde transvenous obliteration · CP: Child-Pugh · EIS: endoscopic injection sclerotherapy · ESLD: end-stage liver disease · EV: esophageal varices · EVL: endoscopic variceal band ligation · GV: gastric varices · HCC: hepatocellular carcinoma · HVPG: hepatic venous pressure gradient · INR: international normalized ratio · MELD: Model for End-stage Liver Disease · NSBB: nonselective beta-blockade · PHG: portal hypertensive gastropathy · SEMS: self-expanding metal stents · TEG: thromboelastography · TIPS: transjugular intrahepatic portocaval shunt · PTFE: polytetraflouroethylene

Introduction Gastrointestinal hemorrhage is a leading cause of mortality in end-stage liver disease. The majority of gastrointestinal bleeding is secondary to rupture of esophageal varices, which develops as a result of portal hypertension. Approximately half of cirrhotics with esophageal varices will develop variceal rupture, and a third of these patients will die from hemorrhage. Given the complexity of this disease process, a multidisciplinary approach is necessary for optimal management of the acutely bleeding patient. Highlighted in this article are evidence-based guidelines for the management of variceal hemorrhage, including endoscopic, radiographic, and surgical treatment modalities. Prophylactic treatment of bleeding and rebleeding are also reviewed, in addition to other, uncommon etiologies of gastrointestinal hemorrhage in cirrhotics.

Cirrhosis and Portal Hypertension Cirrhosis Cirrhosis refers to cellular degeneration and fibrotic changes of the liver parenchyma. (Figure 1) As a sequelae of end-stage liver disease, cirrhosis can develop from a multitude of causes which inflict chronic inflammation within the liver. Alcohol-related and viral insults are the most common causes worldwide.1,2 In the United States, alcoholic cirrhosis and hepatitis C account for the majority of cases. Other causes for cirrhosis include autoimmune hepatitis, bile duct disorders, nonalcoholic steatohepatitis (NASH), hereditary disorders including hemochromatosis and alpha-1 antitrypsin deficiency among others.3

The natural history of cirrhosis can be broadly divided into two phases – the compensated phase and the decompensated phase. In terms of Child-Pugh (CP) classification, class A disease represents compensated cirrhosis, while classes B and C are reflective of decompensated disease. The two phases are demarcated by the development of liver-specific complications, which include jaundice, variceal hemorrhage, refractory ascites, and hepatic encephalopathy.4 Patients with compensated cirrhosis have a greater prognosis compared to their decompensated counterparts. With proper medical management, cirrhotics can remain compensated for many years4, with a median survival of nearly a decade.5 When cirrhotics progress into a decompensated state, their clinical course is punctuated with complications related to metabolic and hemodynamic derangements, and the prognosis becomes grim.

Cirrhosis also predisposes the liver to the development of hepatocellular carcinoma (HCC). In fact, HCC is a major cause of death in compensated disease.6 HCC is more frequently associated with chronic viral hepatitides compared to alcoholic cirrhosis, though both etiologies may lead to malignant degeneration.7

Among the many complications of cirrhosis, portal hypertension is the most severe. There are two mechanisms by which cirrhosis can result in pathologically elevated portal venous pressures. First, chronic inflammation within the liver parenchyma engenders fibrosis and the accumulation of scar tissue. The resultant disruption in

hepatic architecture becomes a mechanical impedance to portal venous flow. Second, cirrhosis causes vascular endothelial dysfunction through various molecular mechanisms.8 The portal and splanchnic venous arcades are most notably affected by this change. Intrahepatic vessels themselves become prone to vasoconstriction, which further contributes to elevated portal venous resistance.9

Portal Hypertension Portal hypertension is defined as a pathologic increase in portal venous pressures. Since direct measurement of portal venous pressure is invasive and impractical, currently, measurement of the hepatic venous pressure gradient (HVPG) is preferred for diagnosis of portal hypertension. HVPG refers to the pressure difference between the intra-abdominal inferior vena cava and the portal veins, and normally ranges from 1 to 5 mmHg.10 HVPG greater than 5 mmHg is diagnostic of portal hypertension.11 Once HVPG increases beyond 10 mmHg, the predictive value of developing complications related to portal hypertension increases dramatically (e.g. clinical decompensation, development of varices).12 Furthermore, HVPG is directly correlated with severity of liver decompensation, variceal size, and risk of variceal hemorrhage.13

Among the various conditions that cause portal hypertension, cirrhosis is the most common, accounting for 90% of cases in the United States alone.14 Since the portal venous obstruction is intrahepatic in nature, cirrhosis is categorized as a sinusoidal cause of portal hypertension. Other causes can be divided into presinusoidal and

postsinusoidal categories, and are listed in Table 1. Presinusoidal causes include schistosomiasis15, mass effect related to tumors, congenital hepatic fibrosis16, and autoimmune diseases such as primary biliary cirrhosis.17 Thrombosis of the portal vein is also classified as presinusoidal, and can result from hypercoagulable states or umbilical sepsis in neonates.18-20 In each of these causes, the liver itself is normal, meaning portal hypertension may occur in the absence of cirrhosis. Postsinusoidal causes are rare and related to pathology within the hepatic veins or the right heart. The most common postsinusoidal cause is thrombosis of the hepatic veins, termed Budd-Chiari syndrome, and develops from hypercoagulable states or myeloproliferative disorders.21 Other causes of postsinusoidal obstruction include inferior vena cava webs, mass effect related to tumors, congestive heart failure, and restrictive pericarditis.

Esophageal Varices Pathophysiology Chronic elevation of portal venous pressures invariably leads to the development of collateral vessels between portal and systemic circuits.22 These collaterals arise from opening of pre-existing vessels, through the impaired clearance of vasoactive molecules22, as well as through angiogenesis.23,24 Portosystemic collaterals can develop throughout the entire body, including the gastrointestinal tract, omentum, diaphragm, bladder, and reproductive organs. 25 Among these, esophageal varices (EV) are the most prevalent in cirrhotics.26 EV connect the portal circuit through the left gastric vein, to the systemic veins, via the

azygous vein and superior vena cava.25 The venous circulation that is affected by portal hypertension leading to variceal formation in the upper GI tract are divided into four gastroesophageal zones.27,28 The gastric zone begins spans from 2 to 3 centimeters caudal to the gastroesophageal junction. Veins in this zone lie longitudinally in the submucosa and lamina propria, draining into the short and left gastric veins of the portal circulation. Perforating vessels connecting the internal and external venous plexus are relatively hindered by the presence of developed gastric muscularis mucosae. The palisade zone, which normally is the transition between portal and systemic venous drainage, begins caudally at the gastroesophageal junction and ends at the diaphragmatic hiatus. In this zone, veins in the lamina propria lie in parallel longitudinal palisades and flow into the coronary, azygos and hemiazygos veins. Few perforating vessels are connecting palisades to parallel submucosal veins within the esophageal mucosal rugae. The perforating zone extends 2 cm cranially from the hiatus of the thoracic esophagus where perforating vessels again pierce the esophageal wall and connect the mucosal vessels to the lamina propria vessels. Lastly, the truncal zone is most cranial and extends 8 to 10 cm up the thoracic esophagus and contains irregular perforating vessels that connect the submucosal venous plexus to the longitudinal veins in the lamina propria.

Epidemiology and Natural History EV are present in 50% of cirrhotics.26 The prevalence of EV among cirrhotics varies based on the severity of liver decompensation, ranging from 40% among CP class A, to 85% in class C cirrhotics.26 The annual incidence of EV is 5-10%.29 Once EV develop, their natural tendency is to grow in size30, increasing at a rate of 20% every 18 months.31 (Figure 2)

Large varices are prone to rupture.32 About 50% of cirrhotic patients with EV, and a third of non-cirrhotic patients with EV, will experience at least one episode of variceal hemorrhage.33,34 Risk factors for variceal rupture include EV diameter, red wale marks, and decompensated liver disease.32,34 Among these factors, large variceal size is the most important predictor of hemorrhage, with an estimated 15% annual risk for varices measuring >10 mm in diameter.30 Management of acute variceal bleeding requires a multidisciplinary approach requiring coordination between intensivists, gastroenterologists, surgeons, interventional radiology, and auxiliary staff. Care of these patients is most appropriate in the intensive care unit with experienced practitioners.

Mortality from Variceal Hemorrhage Variceal hemorrhage is often complicated by coagulopathy and thrombocytopenia related to liver disease.35 Indeed, a third of those who suffer from ruptured EV will die as a result.29,36-38 Among those that survive, 60% will develop recurrent bleeding.29,39 Median survival is estimated at less than two years after the

appearance of EV.29 Risk factors for early mortality include Child-Pugh and Model for End-Stage Liver Disease (MELD) scores40, active hemorrhage on admission41, HVPG greater than 20 mmHg42, and concomitant bacterial infection.43 Approximately 1/3 of all cirrhosis related deaths are due to upper GI bleeding from variceal disease.29

Two models have been developed to predict overall mortality with end-stage liver disease – Child-Pugh classification and MELD scoring systems. MELD is a logarithmic equation which accounts for bilirubin, international normalized ratio (INR), and creatinine levels, with exception for recent dialysis. Initially formulated to predict 90-day mortality rates in patients undergoing elective transjugular intrahepatic portocaval shunting (TIPS) procedures, it has since been expanded to predict overall survival in cirrhotic patients with infection, fulminant liver failure, and variceal hemorrhage.44 Similar to MELD, the Child-Pugh classification system was designed to predict one-year and two-year survival rates in cirrhotics.45,46 It measures INR, bilirubin, and albumin levels; but also accounts for the presence of clinical factors including ascites and encephalopathy. Class A cirrhotics are predicted to have a 100% one-year survival rate, which falls to 81% in class B and 45% in class C cirrhotics.45 As previously mentioned, class A is representative of compensated disease, while classes B and C reflect decompensated cirrhosis. Both scoring systems have been equally efficacious in predicting overall mortality.47

Primary Prophylaxis Given that variceal hemorrhage carries a significant rate of morbidity and mortality, identification and prophylactic treatment of EV are of paramount importance. Thus, screening endoscopy is advocated in all cirrhotics.33,48 Compensated patients without EV should repeat surveillance endoscopy in three-year intervals. If there is ongoing liver injury, this interval should be shortened to two years.49 Similarly, compensated patients with small varices (<5 mm) should undergo surveillance endoscopy in two-year intervals, with annual surveillance recommended for ongoing liver injury.49

If medium (5-10 mm) or large-size EVs (>10 mm) are found during screening endoscopy, prophylactic treatment is indicated. There are currently two accepted modalities for prophylactic treatment of varices – endoscopic variceal band ligation (EVL) and nonselective beta-blockade (NSBB). Both modalities have been equally efficacious in preventing variceal hemorrhage when compared in clinical trials.50-52 EVL can be performed at time of surveillance endoscopy, and involves the placement of rubber bands around dilated vessels until they are ablated. Endoscopic treatment has been shown to decrease the risk of hemorrhage and overall mortality in cirrhotics.53 EVL is recommended over sclerotherapy, as EVL has demonstrated higher rates of variceal eradication, fewer complications, and lower rates of rebleeding.54

NSBB (e.g. timolol, nadolol, propranolol) works synergistically through three separate receptors. Beta-2-receptor blockade results in splanchnic vasoconstriction, beta-1-receptor inhibition causes a decrease in cardiac output; and subsequent, unopposed alpha-1 activity decreases portal venous pressures.55 Reduction of HVPG by 10% has proven to be effective in preventing variceal hemorrhage.12 However, in practice, NSBB does not always reduce HVPG.56 One study noted a 50% response rate in portal venous pressures to NSBB.56 Additionally, NSBB have proven ineffective in preventing the development of EV in cirrhotics without varices.11

Effective prophylactic treatment of EV can reduce the risk of hemorrhage by as much as 50%.57 Clinical guidelines for the treatment of asymptomatic EV have been established by the Baveno Consensus Workshop, with the most recent revisions made in 2015.49 In cirrhotics without EV, NSBB is not recommended, as pharmacotherapy may cause adverse events and do not prevent the development of varices. Cirrhotics with small varices at no risk of bleeding may be treated, but further studies are needed. Those with small varices at increased bleeding risk (i.e. red wale marks, decompensated disease) should be started on NSBB. If medium or large-sized varices are noted on endoscopy, either endoscopic or pharmacologic therapy is recommended. Sclerotherapy and shunt procedures are reserved for acute hemorrhaging episodes, and not indicated for prophylactic treatment.

Before proceeding with prophylactic treatment, one must consider the risks and adverse effects associated with the use of NSBB. Additionally, hospital equipment

and availability of personnel may preclude the cirrhotic patient from receiving adequate endoscopic treatment. Therefore, the choice of treatment is largely dependent upon hospital and patient factors.

Secondary Prophylaxis Among survivors of variceal hemorrhage, 60% will develop rebleeding29,39, and a third of rebleeders will die with each hemorrhaging episode.58 Thus, prophylactic treatment of rebleeding is as crucial to medical management as primary prophylaxis. Treatment modalities for secondary prophylaxis primarily include shunting procedures and transplantation, in addition to NSBB and EVL. As with primary prophylaxis, NSBB has been shown to decrease rates of variceal rebleeding.59-61 Studies comparing endoscopic therapy with pharmacologic therapy alone have found no difference in rebleeding risk or mortality62-64, however, the combination of NSBB and EVL is superior when compared to monotherapy for prevention of rebleeding.65,66

Clinical guidelines from the Baveno Consensus Workshop provide recommendations for the prevention of recurrent variceal bleeding.49 First-line treatment for rebleeding prophylaxis is combination EVL and NSBB therapy. EVL monotherapy is not indicated unless there are contraindications to NSBB, or beta blockade is otherwise poorly tolerated. Similarly, NSBB monotherapy is indicated only if endoscopic treatment is not feasible. If the cirrhotic develops recurrent

hemorrhage despite combination treatment, then covered TIPS placement is indicated, as discussed in the TIPS section.

TIPS has been shown to dramatically decrease rebleeding rates compared with EVL/NSBB, but increases the incidence of hepatic encephalopathy and does not increase overall survival.67 Thus, TIPS insertion is not recommended as first-line therapy for secondary prophylaxis.68 Like TIPS, surgical portosystemic shunts have been shown to decrease rebleeding and increase encephalopathy without any change in mortality rates.69,70 Failure of shunting procedures to prevent rebleeding may be cause for liver transplantation.

Other Causes of Gastrointestinal Hemorrhage in Cirrhotics

Classification Esophageal varices are the most common cause of gastrointestinal hemorrhage in cirrhotics, accounting for 60-65% of cases, but a multitude of other etiologies may result in bleeding as well.33 These lesions can be classified into those related to portal hypertension, and those seen in the general population (Table 3).71 Portal hypertension-related lesions include esophageal varices, gastric varices, ectopic varices, and portal hypertensive gastropathy. Unrelated lesions include bleeding peptic ulcers, reflux esophagitis, erosive gastritis, malignancy, and Mallory-Weiss tears; and will not be reviewed here.

Gastric Varices Gastric varices (GV) are the second most common cause of gastrointestinal hemorrhage in cirrhotics, accounting for 5-10% of cases.72 GV are present in approximately 20% of cirrhotics.73 These varices connect the portal circulation, through left gastric, short gastric, and posterior gastric veins; to the systemic circulation.25

GV may occur alone or in combination with esophageal varices, and can be classified into gastroesophageal or isolated gastric varices. Type 1 gastroesophageal varices are the most common type, accounting for 75% of GV, and occur along the lesser curvature of the stomach. Type 2 gastroesophageal varices lie along the greater curvature, and are highly susceptible to hemorrhage. Isolated gastric varices are also subdivided into two types. Type 1 isolated gastric varices exist in the fundus and are prone to hemorrhage, with a nearly 80% bleeding rate, whereas type 2 varices occur anywhere outside of the fundus and rarely rupture.73 If isolated gastric varices are seen on endoscopy, then portal vein and splenic vein thrombosis should be evaluated as a potential cause.55 Altogether, GV bleed less frequently but more severely compared with their esophageal counterparts.30

Data on the treatment of acutely bleeding GV is limited. Pharmacologic therapy with terlipressin or somatostatin is recommended and endoscopic injection of cyanoacrylate is the therapeutic treatment of choice. 74-76 Control of bleeding occurs in up to 90% of patients. EVL and sclerotherapy have been reported as alternatives

to cyanoacrylate injections with conflicting results.77,78 Currently injection remains the first line endoscopic therapy for patients with acutely bleeding GV. TIPS is also highly effective with control of bleeding in greater than 90% of patients, however, is reserved for those failing endoscopic management.

Portal Hypertensive Gastropathy Portal hypertensive gastropathy (PHG) refers to diffuse venous dilations within the stomach, which are present in up to 80% of those with portal hypertension.79 These vessels are susceptible to erosion and hemorrhage, as the overlying gastric mucosa is sensitive to injury and heals poorly.80 Clinically, PHG presents as either acute hemorrhage or chronic bleeding.80 This disease process is responsible for <1% of gastrointestinal hemorrhage in general population, and 2-10% in those with portal hypertension.81,82

The pathogenesis of PHG is related to portal hypertension but not completely understood.83 Hyperdynamic splanchnic circulation is theorized to increase total gastric flow and decrease gastric mucosal flow, which results in dilated gastric veins with poorly healing mucosa.80 The main predictors of PHG include severe liver dysfunction and portal hypertension, which support this hypothesis.83 Furthermore, the severity of PHG correlates with the degree of portal hypertension and related parameters, such as HVPG.84,85 Some studies have even noted that eradication of EV results in increased incidence and severity of PHG.86

As with other causes of gastrointestinal hemorrhage, PHG is diagnosed with upper endoscopy, which reveals a mosaic pattern of erythema within the gastric lumen.80 The mosaic erythema reflects the presence of dilated veins, and can be found in the gastric fundus, body, and antrum.87 Classification schemes grade the degree of PHG based on presence of characteristic endoscopic findings, including mosaic-like pattern of erythema, red-pointed lesions, cherry red spots, and brownish/blackish spots.88 Unlike GV, acute hemorrhage from PHG is not as profuse as ruptured EV.30 Chronic bleeding is manifested through iron-deficiency anemia.89,90 Because the risk of bleeding from PHG is low, primary prophylaxis is not necessary. In patients with recurrent or chronic bleeding, propranolol is the pharmacologic agent of choice for secondary prophylaxis.

Ectopic Varices Ectopic varices are defined as large portosystemic collateral veins located anywhere outside of the esophagogastric region.25 These varices exist predominantly throughout the alimentary tract, omentum, biliary tract, diaphragm, urinary bladder, uterus, and vagina.25 Rectal varices are the most common, followed by varices within the small intestine.91

Ectopic varices are rare, with a mere 3.5% prevalence among those with portal hypertension.91 They account for 1-5% of gastrointestinal hemorrhage in cirrhotics, presenting as both upper and lower GI bleed depending on the location of the ruptured varix.92,93 Bleeding from ectopic varices is often massive and life-

threatening, with an estimated 40% mortality rate from ruptured duodenal varices.91 Since these lesions are often located in inaccessible locations, diagnosis and treatment may be delayed. Endoscopic evaluation is key for the diagnosis of ectopic varices in patients with portal hypertension. In these patients, duodenal evaluation on upper endoscopy must be performed. Jejunal varices may be diagnosed via double-balloon enteroscopy or capsule endoscopy. Varices of the lower gastrointestinal tract may be identified on colonoscopy or rigid protoscopic examination. The clinician should maintain a high suspicion for ectopic varices in cirrhotics with gastrointestinal hemorrhage. Treatment of ectopic varices is similar to that of esophageal variceal management beginning with initial stabilization and resuscitation, pharmacologic treatment, endoscopic intervention, and surgical treatment for failures.

Resuscitation and Stabilization following Variceal Rupture If variceal bleeding is suspected, initial measures may include airway protection, hemodynamic monitoring, blood product resuscitation, pharmacologic therapy and balloon tamponade. These measures are aimed at stabilization of the patient and bridging to definitive diagnosis and therapy. (Figure 3)

Resuscitation Severe acute variceal bleeding most often requires volume resuscitation and blood transfusion. A restrictive blood transfusion strategy with hemoglobin thresholds of

7 g/dL rather than 9 g/dL has been shown to improve survival for severe upper GI bleeding.94 Decompensated liver disease complicates resuscitation due to inability to tolerate volume shifts and susceptibility to dilutional coagulopathy.

Correction of underlying coagulopathy in patients with severe hepatic dysfunction may prove to be difficult because prothrombin and partial thromboplastin times do not always correlate with the severity of coagulopathy. Studies have suggested that a rebalanced hemostasis exists in some patients despite thrombocytopenia and elevated prothrombin time/international normalized ratio. Platelet aggregation studies and thromboelastography (TEG) can be employed to guide correction of coagulopathy in the face of hemorrhage and chronic liver dysfunction.95

Resuscitation strategies for variceal bleeding benefit from conservative volume expansion due to increased risk for recurrent bleeding when the splanchnic venous circuit has been overexpanded. Evidence borrowed from trauma literature suggests that volume expansion to a goal systolic blood pressure of 70-100 mm Hg may improve survival in the actively hemorrhaging patient.96 Markers of adequate resuscitation should be followed as is standard, including placement of a Foley catheter in order to monitor urine output.

Pharmacologic intervention Initial pharmacologic therapy may include continuous intravenous infusion of somatostatin analogues. Octreotide bolus of 50 µg followed by continuous infusion at 50 µg/hr has emerged as the treatment of choice to reduce portal venous pressure and portocollateral flow with few side effects.97

Vasoconstrictive therapy, including use of both vasopressin and terlipressin, has been well studied as adjunct therapy for acute variceal bleeding. While terlipressin, a synthetic analogue of lysine-vasopressin, is the only primary pharmacologic therapy that has been shown in randomized trials to improve overall survival, this drug is not widely available. Furthermore, both vasopressin and terlipressin have a larger adverse effects profile when compared with somatostatin. 98

A meta-analysis evaluating the efficacy of octreotide in acute esophageal variceal bleeding has shown that, although the addition of octreotide did not reduce overall mortality following acute bleeds, it was successful in reducing the risk of rebleeding from 32% from 19% in patients receiving endoscopic or decompressive therapy for acute variceal bleeding.99

Balloon tamponade

Balloon tamponade emerged as an important adjunct therapy for the stabilization of severe gastroesophageal variceal bleeding. Since its introduction by Westphal in the 1930s the Sengstaken-Blakemore tube is the most popular technique for tamponade of acute gastroesophageal variceal bleeding.100 (Figure 4) The SengstakenBlakemore device is a triple-lumen tube made of flexible plastic that consists of two balloons and a gastric port used to aspirate gastric contents. A modern adaptation of this is the Minnesota tube, consisting of 4 lumens which allow for aspiration of both gastric and esophageal contents.

Endotracheal intubation and gastric lavage may be required prior to the use of this technique. Once the airway is secured, the tamponade balloon can be inserted nasally or orally to a gastric position of at least 50 cm. The gastric balloon is inflated with 200 ml air and retracted snugly against the gastric inlet. If bleeding continues despite cranial traction on the gastric balloon, the esophageal balloon may also be inflated to a pressure of 40 mm Hg. The tube is then secured with external traction to the skin or other device. An additional nasogastric tube may be inserted to the depth of the esophageal balloon to monitor for bleeding. Alternatively, the Minnesota tube includes an esophageal aspiration port, in addition to its gastric counterpart.

The use of balloon tamponade has been complicated by the potential for inappropriate positioning, inadequate or excessive balloon inflation, and migration

of the gastric balloon. Additionally, esophageal perforation, airway obstruction and mucosal ulceration have been reported.101 Once implemented, the use of balloon tamponade mandates more definitive measures to decrease the chance of rebleeding within the first 12-24 hours, usually by way of TIPS. Initial control of bleeding episodes is as high as 80%, however rebleeding is common if additional measures are not taken.

Endoscopy Endoscopy is the mainstay of diagnosis and treatment of upper GI bleeding for those in whom esophagogastric varices are suspected.102 Emergent endoscopy is recommended and should be completed within the first 12 hours of presentation. Diagnostic endoscopy can become therapeutic if variceal bleeding is confirmed. Endoscopic diagnosis of acute variceal bleeding is made by the confirmation of hemorrhage or stigmata of recent bleeding from varices. Diagnostic endoscopy is also employed to determine the size and extent of varices and prognostic factors of acute bleeding and rebleeding.34 The goal of endoscopic therapy is to obliterate the varix thereby decreasing variceal wall tension. Endoscopic therapy for acute variceal bleeding should be used in combination with pharmacologic, endovascular and surgical therapies to prevent rebleeding.

History Endoscopic therapy for acute variceal bleeding has evolved since endoscopic injection sclerotherapy was first reported by Crafoord and Frenckner in 1939 though its use was not widely adopted until the 1980s as portovenous shunting lost favor.103 The replacement of rigid endoscopy with flexible fiberoptic endoscopes hastened the widespread adoption of endoscopic techniques in this patient population. Between 1980 and 2000, the use of endoscopic therapy for acute variceal bleeding increased from 6% to 90%. In one center, adoption of new techniques during this time period decreased mortality of acute variceal bleeding from 70% to 32% in patients with CP class A and B liver disease.104

Endoscopic Injection Sclerotherapy (EIS) Sclerotherapy achieves hemostasis by inducing inflammatory reactions in the variceal lumen and surrounding tissues, leading eventually to mural necrosis and variceal obliteration. Sodium tetradecyl sulfate, morrhuate sodium, ethanolamine and ethanol have been used successfully as sclerosants.105 Endoscopic injection of tissue adhesives have also been used in conjunction with endoscopic injection sclerotherapy for gastric fundal varices, which have lower success rates with EIS alone. Some studies have shown endoscopic injection of cyanoacrylate tissue adhesives have been shown to be more effective than ethanolamine for these gastric fundal varices.106

Technique Diagnostic and therapeutic endoscopy requires intravenous sedation, and can be done in the endoscopy suite or at the patient bedside with appropriate monitoring. Once the decision to proceed with therapeutic endoscopy is made, the diagnostic gastroscope is replaced by a double-channel gastroscope. A balloon catheter inflated with 200 cc of air and pulled against the gastroesophageal junction can be used to decrease the rate of variceal bleeding if acute hemorrhage obscures visualization. A small amount of sclerosant (about 2 cc) is then injected directly into the lumen of the varix. Some practitioners will also perform paravariceal injections, which have also proven effective for variceal obliteration. The total number of injections is limited to fifteen during a single procedure, in order to limit the volume of sclerosant used. In addition to endoscopic therapy, balloon tamponade can be used for up to 5 minutes with each injection to slow the rate of bleeding. Due to the risk for esophageal perforation, chest x-ray should be obtained within 24 hours of the procedure.107

Outcomes Initial therapy by injection sclerotherapy achieves hemostasis in 70-85% of cases. Repeat bleeding is observed in greater than 30%. Sclerotherapy is superior to medical management alone in acute variceal bleeding.107 While some authors advocate repeat sclerotherapy, the reduced efficacy of repeated injections is well established and may pose increased risk to the patient with no improvement in

hemostasis.108 Complication rates following endoscopic sclerotherapy are as high as 50% and include bleeding, esophageal and gastric wall necrosis, esophageal strictures and pseudodiverticula, distal esophageal mucosal bridges, mediastinitis, pneumonitis, and transient bacteremia.105 Potential adverse reactions to sclerosing agents including fever, pleural effusion, chest pain and anaphylaxis.109 Due to the success of variceal ligation, EIS is now typically reserved for cases in which ligation is not possible or has been attempted and failed.

Endoscopic Variceal Band Ligation (EVL) Endoscopic band ligation of esophagogastric varices is a newer alternative technique for management upper GI varices with relatively fewer complications. Endoscopic band ligation of varices avoids the use of sclerosant by mechanically restricting flow into varix, however microscopic examination of the treated sites in fact show ischemic necrosis of the mucosa and submucosa, acute inflammation and formation of granulation tissue. The technique was first reported by Steigmann in 1988.110

Technique Band ligation can be performed immediately following diagnostic endoscopy. Elastic banding devices include a vacuum assisted cap, which captures the target tissue for

banding and a delivery mechanism places one to two small elastic bands over the tissue. (Figure 5) There is some variation in banding devices available including the presence of accessory and irrigation ports and single band and multiband capabilities. If using a single band ligation device, a plastic sheath should be placed in the esophagus to facilitate repeated passages of the endoscope and banding device into the distal esophagus.25 Varices are approached from distal to proximal to ensure adequate visualization as variceal columns are banded. The first band is typically placed just below the gastroesophageal junction and banding is continued up to 7.5 cm above the gastroesophageal junction to obliterate the variceal column.105

Outcomes EVL has been shown to achieve similar degrees of hemostasis during acute bleeding and is more effective in preventing rebleeding compared to endoscopic injection sclerotherapy. Ligation is associated with lower complication rates and improved overall survival for CP class A and B patients than injection sclerotherapy. Mortality in CP class C patients is equivalent in both techniques with deaths resulting primarily from decompensated liver failure.110,111 Compared to injection sclerotherapy, fewer treatment sessions are needed for complete obliteration of the varices when using ligation.

Adjunct Therapies Endoscopic therapy achieves hemostasis in 90% of patients with acutely bleeding esophagogastric varices, however, the probability of recurrent bleeding may be as high as 50%. Pharmacological therapy (terlipressin, somatostatin) should be continued for 5 days following endoscopic therapy and antibiotic prophylaxis is recommended to prevent complications such as spontaneous bacterial peritonitis.102,112 The continuation of NSBB and nitrates (isosorbide mononitrate) is recommended following endoscopic intervention to aid in lowering portal pressures, decreasing development of recurrent varices, and ultimately preventing acute bleeding episodes.113 Carvedilol is more effective than traditional nonselective beta blockers, propranolol and nadolol, at lowering hepatic venous pressure gradient.114 Selection of the beta blocker must be tailored to the hemodynamic tolerance of the patient to each agent.

Self Expanding Stents New studies suggest the use of endoscopically placed self expanding stents may be a safer alternative to balloon tamponade for refractory variceal bleeding.115,116 Removable, covered, self-expanding metal stents (SEMS) have a number of advantages over other salvage techniques for difficult variceal bleeding. Deployment of the stent requires fewer resources and can be done without intravenous contrast or fluoroscopy. There is no requirement of endotracheal intubation and oral nutrition may be continued. Compared to portosystemic shunting, there is no

increased risk of hepatic encephalopathy. Available data suggest the risk of esophageal perforation is low and retrieval of SEMS is uncomplicated.117 SEMS should be used as a bridge to more definitive control of portal hypertension and gastroesophageal varices due to the high rate of rebleeding after conservative management and SEMS removal. This technique is still largely investigational and has not gained widespread acceptance.

Balloon-Occluded Retrograde Transvenous Obliteration (BRTO) of Gastric Varices Gastric variceal bleeding represents only 20-30% of all variceal bleeding but presents a unique challenge that often requires a multidisciplinary approach to reliably stop bleeding.118 Acute bleeding from predominantly gastric varices is less amenable to portal decompression by means of TIPS. Gastric varices related to portal hypertension are often associated with spontaneous formation of gastrorenal or gastrocaval shunts. The development of balloon-occluded retrograde transvenous obliteration or “BRTO” has allowed for advancements in control of these varices. Varices are accessed by way of the newly formed shunts and are obliterated with the use of endovascular balloon occlusion and injection of sclerosing agents. (Figure 6) The technique was first performed in the early 1990s and reported by Kanagawa in 1996.119 An alternative technique from a percutaneous transhepatic approach is called balloon-occluded antegrade

transvenous obliteration (BATO) and can be considered as an adjunct to BRTO and endoscopic therapies. 120

Technique The technique for BRTO has been refined in Japan over the course of the last two decades as an alternative or adjunct to endoscopic management of gastric varices.121 Patient selection and vascular anatomy is critical in the technical success of BRTO. Gastrorenal shunts are absent in 15-60% with gastric varices. Some shunts may be too large to be occluded by currently available balloon catheters and are not amenable to the procedure. For patients with appropriately sized shunts, venous access is obtained most commonly via the right femoral vein, although some centers have adopted an internal jugular approach. Access to the gastrorenal shunts is obtained through the left renal vein. A number of manufacturers produce occlusion balloon catheters with balloon diameters ranging from 8.5 to 32 mm. Full occlusion of the shunt outflow is critical to deliver high concentrations of the sclerosing agent to the varix without leak into the circulation. Balloon occluded retrograde venography is performed prior to injection to define the anatomy of the venous drainage. Drainage into one or two distinct shunts are most amenable to BRTO.

A microcatheter is passed beyond the occlusion balloon as deep as possible into the varix. Sclerosing agents are infused to fill the afferent portal vasculature. Ethanolamine oleate (EO) was originally described as the agent of choice for BRTO

and is still commonly used around the world. Major side effects include intravascular hemolysis and, less commonly, cardiogenic shock, pulmonary edema, and disseminated intravascular coagulation. Sodium tetradecyl sulfate (STS), polidocanol foam and coil embolization are popular alternatives that are available and used broadly in a variety of vascular beds in the United States. (Figure 7) Small collateral veins such as inferior phrenic or paravertebral veins may be occluded using standard embolization techniques. The presence of multiple dominant shunts may require placement of additional occlusion balloons and is beyond the scope of this text.

Occlusion balloons are left in place for 4 hours to allow for complete obliteration of the vessel by the sclerosing agent, failure of BRTO to obliterate a varix may be due to incomplete occlusion. Balloon deflation occurs under fluoroscopy prior to removal.

Outcomes The technical results of BRTO/BATO in appropriately selected patients is 84100%.122 Technical failures are largely related to inability to cannulate and occlude the shunt or failure to opacify the varix with contrast/sclerosant. Balloon rupture has also been reported in up to 8% of cases. Long term results for BRTO is limited. Recurrence of gastric varices was 2.7% with 1.5% incidence of recurrent bleed within 5 years.123 While some patients suffer from worsening esophageal varices after BRTO, these are more likely amenable to primary endoscopic therapy. Some

studies suggest improvement in hepatic encephalopathy and hepatic function for 612 months following BRTO, however return to baseline liver function is expected within 3 years. Decompensated liver disease and the presence of hepatocellular carcinoma are prognostic of poor survival following BRTO.

Transjugular intrahepatic portosystemic shunt (TIPS) For patients who continue to bleed from their varices despite pharmacologic and endoscopic intervention or who experience rebleeding, a portal decompressive procedure is indicated. TIPS has emerged as the first-line treatment for bleeding esophageal varices in this setting. The evolution of TIPS began in the 1960s when inadvertent access of the portal system occurred during transjugular cholangiography. Following this, animal studies were carried out to explore the use of transhepatic portal access for creation of an intrahepatic shunt. This was first accomplished in dogs by way of the right jugular vein and through the use of a series of dilating catheters. After sequential dilations a sleeve was left across the tract such that a shunt was created between the portal and systemic systems. 124 (Figure 8) Early animal models were met with significant patency failures due to the lack of pressure from portal hypertension and the weak internal scaffolding that normal liver parenchyma provides.125 In the 1988, the first human TIPS procedure was performed utilizing bare-metal, expandable stents. 126 By the early 1990s TIPS was widely used for the management of bleeding varices in the setting of portal hypertension, however long term results were plagued by patency failures. In the

late 1990s into the early 2000s the advent of e-PTFE covered stents dramatically improved patency rates. TIPS has now become the most commonly performed portosystemic shunt procedure in the United States. While the development of TIPS was directed for the management of variceal bleeding, patients with concomitant ascites were found to have resolution following TIPS – this has now become the most common indication for TIPS with close to 90% of all TIPS procedures performed electively. 127 Considering that many candidates for TIPS are also potential liver transplant candidates, one major advantage of TIPS is the in-vivo removal of the shunt during liver transplantation, thus avoiding the complications from prior intra-abdominal surgery as well as the need for ligation or revision of the shunt following the transplant procedure.

Technique TIPS procedures are primarily performed by interventional radiologists. Preprocedural planning includes cross-sectional imaging for identification of portal anatomic variants and ultrasound confirmation of portal patency. All patients with large-volume ascites should be drained prior to the procedure to restore proper anatomic positioning of the liver, aiding in obtaining successful transvenous hepatic punctures and in reducing blood loss from potential capsular violations. Some absolute contraindications to TIPS include congestive heart failure, severe pulmonary hypertension, uncontrolled sepsis, and biliary obstruction. Evaluation of underlying liver disease should be completed prior to referral as survival benefit for patients with MELD scores >22 is unclear. 128,129

The procedure begins with wire-guided access to the hepatic venous system via the jugular vein through the superior vena cava into the right atrium, inferior vena cava and finally into a hepatic vein. After access to the hepatic venous system, the catheter enters the hepatic parenchyma and is guided towards the portal vein. Ultimately a tract is formed joining the hepatic venous system to the portal system. Once entrance to the portal system is established, portal imaging is obtained to confirm intrahepatic portal entry. Pre-dilation of the tract is performed using angioplasty balloon followed by deployment of a stent graft which can range from 812 mm in diameter and is ideally 1 – 1.5 cm longer than the measured distance between the portal vein entry site to the hepatic vein/IVC junction. 3,127 This newly formed connection creates a side-to-side portocaval shunt thus reducing portal pressures to a goal of <12 mmHg.

Outcomes Cessation of variceal bleeding occurs in 90-100% of patients undergoing TIPS with the incidence of recurrent bleeding occurrences as low as 10%, however, long term survival remains unchanged.3 Hepatic encephalopathy continues to be the most common complication following TIPS and occurs in 30-40% of patients with 5-10% of patients experiencing chronic, recurrent, disabling encephalopathy. 69,130 The incidence of encephalopathy increases as the degree of liver failure progresses. The risk of accelerating liver failure by way of reducing hepatic blood flow remains between 3% and 5% and is associated with a residual portal gradient of less than 5

mm Hg. 129,131 TIPS stenosis and occlusion was a common complication in the early years of TIPS occurring in 50% to 60% of cases within the first year. Patency was maintained with ongoing surveillance and redilation as needed.3 Acute thrombosis of the stent occurring shortly after the procedure is often due to a technical failure while delayed occlusion is likely due to neointimal proliferation. Neointimal proliferation is the growth of collagenous tissue between the stent and the endothelial surface of the stent. (Figure 9) Hemodynamic changes become significant when the stenosis exceeds 50% narrowing. 132 This complication was greatly mitigated with the introduction of e-PTFE covered stents, increasing primary patency from 36% to 76% at 2 years. Currently, expandable PTFE-covered stents are the standard of care for patients undergoing a TIPS procedure. 69 Mortality following TIPS from uncontrolled variceal hemorrhage ranges from 27%50% and is associated with Child C status, increasing MELD score, and hemodynamic instability at the time of TIPS. 133,134 Due to the risk of hepatic encephalopathy and no associated increase in long-term survival, TIPS remains a secondary prevention measure for bleeding esophageal varices. Decompression of the portal system through a relatively non-invasive approach has revolutionized the care for these critically ill patients.

Surgical Decompression There are three main types of surgical decompression for the treatment of bleeding varices including surgical shunt creation, liver transplantation, and devascularization procedures. The first account of surgical decompression for portal

hypertension was described and performed on animals in the late 1800s by Nikolai Eck for the study of diseases of the liver. The “Eck” fistula is a large side-to-side connection of the portal vein and vena cava (at least 12mm) with subsequent ligation of the portal vein just as it enters the liver. Report of the first clinically successful use of the Eck fistula was in 1903 by Vidal.135 However, it was at the Splenic Clinic at the Presbyterian Hospital in New York that portosystemic shunting for the treatment of varices from portal hypertension gained traction. Dr. Alan O. Whipple and his group experimented with numerous types of portosystemic shunts for the treatment of bleeding varices. Their early years were met with many failures and it was not until 1945 that Whipple and Blakemore reported the first successful account of a central surgical shunt for the treatment of bleeding varices.136 Initial enthusiasm for the procedure was high, as it was believed that it cured patients of their esophageal varices with little to no risk of recurrent bleeding. During the mid20th century surgical shunts were performed prophylactically in those patients with evidence of varices due to portal hypertension. Although successful at preventing variceal bleeding and subsequent bleeding-related deaths, a critical evaluation of overall survival of patients with a portosystemic shunt revealed their mortality rate to be similar to those patients who had not undergone a shunt procedure. It was discovered that those patients who had undergone a shunt procedure were dying from hepatic failure at a rate similar to those dying due to uncontrolled hemorrhage without a shunt procedure. 137-139 Additionally, up to 50% of patients were suffering from hepatic encephalopathy due to reduced portal perfusion. Consequently, the use of shunts as a prophylactic measure for varices was quickly abandoned. Despite the

dismal long-term results, central shunting remained the only effective option for prevention of variceal bleeding and its recurrence until the introduction of selective portosystemic shunts in the mid to late 1980’s. Through the use of selective shunts, the esophagogastric system was adequately decompressed with the preservation of portal perfusion, avoiding the effects of hepatic encephalopathy and impending hepatic failure. Selective shunts quickly became the most common portosystemic shunting procedures performed until the advent of endoscopic interventions, TIPS, and the popularization of hepatic transplantation as definitive treatment for patients with end-stage liver disease 140 For patients unable to undergo selective shunting due to anatomic considerations, surgical devascularization, popularized in the East, emerged as an alternative for these patients.139 Although they have lost much popularity, portosystemic surgical shunts remain an option for long-term bridge to transplant in those patients with preservation of hepatic reserve and for those who fail medical management. 141

Non-Selective Surgical Shunts

Totally Diverting Shunts Totally diverting shunts completely divert portal flow from the liver by joining the portal vein, or a major branch, to the inferior vena cava or one of its major branches. These include the end-to-side portacaval shunt or “Eck” fistula, large diameter sideto-side portocaval shunt, side-to-side mesocaval shunt, and the central splenorenal shunt. Pressures in the vena cava are significantly lower than that of the portal

venous system creating a reversal or “hepatofugal flow”. This reversal of flow into the caval system reduces the overall portal pressures and often reduces high hepatic sinusoidal pressures. Totally diverting shunts have patency rates as high as 98% and control acutely bleeding esophageal varices in 95-100% of cases.142,143 This excellent control of bleeding varices occurs at the expense of total hepatic perfusion with risk of hepatic failure rivaling the 50% risk of mortality that accompanies a first-time variceal hemorrhage.138 Furthermore, the rate of encephalopathy from totally diverting shunts can be as high as 40-50%, significantly affecting the quality of life for these patients. 140

Since the development and widespread use of total shunts, liver transplantation has gained traction as a long-term solution for patients living with end-stage liver disease. While total shunts may be used as a bridge to transplant in those patients with refractory bleeding, they may lead to a more difficult transplant procedure due to the significant dissection necessary around the porta hepatis, and the need for shunt reversal at the time of transplant. The current indications for total portosystemic shunts procedures include bleeding esophageal or gastric varices and bleeding from PHG that is unresponsive to pharmacologic management, Budd-Chiari syndrome, intractable ascites unresponsive to nonsurgical therapy, and failed TIPS procedures. Contraindications include long-standing portal vein thrombosis, portal vein thrombosis in the face of normal liver architecture, and hepatic artery occlusion.

End-to-Side Portacaval Shunt (Eck Fistula) In this totally diverting shunt procedure the portal vein is divided at the hilum of the liver followed by suture ligation of the hepatic stump. The proximal, or splenic limb is then sewn to the side of the vena cava making sure to maintain a large diameter anastomosis.143 All portal flow is diverted around the liver and into the caval system by way of the splenic limb of the portal vein. Perfusion of the liver is completely dependent on the hepatic artery, and, significant risk of hepatic failure follows. Due to the complete interruption and ligation of the hepatic limb there is no portal outflow tract created and as a result high pressures within the sinusoidal beds may persist causing a potential worsening of ascites.3 While this was the first totally diverting shunt to be described, its use is rare in the modern era of surgical decompression.

Side-to-Side Portacaval Shunt Large-diameter side-to-side portacaval shunts differ from end-to-side total shunts in that the portal vein is not transected and ligated in this approach. Instead, both the portal vein and inferior vena cava are mobilized and oriented parallel to one another such that the side of the portal vein is anastomosed to the side of the inferior vena cava. The low-pressure caval system creates a reversal of flow away from the liver (hepatofugal flow). (Figure 10) The portal vein now serves as an outflow tract from the liver towards the caval system successfully decompressing both the splanchnic portal system and lowering the pressures within the hepatic sinusoidal beds. Bleeding from varices immediately resolves and due to the

lowering of hepatic sinusoidal pressures, resolution of ascites is also seen in these patients. This is the shunt of choice in Budd-Chiari patients with post hepatic portal hypertension.

Mesocaval Shunt The third totally diverting shunt is the mesocaval shunt. The portal system is decompressed via the superior mesenteric vein into the inferior vena cave through an end-to-side or side-to-side anastomosis or by way of a large-diameter interposition shunt. The end-to-side mesocaval shunt has been used primarily in children with portal vein thrombosis. The inferior vena cava is ligated just proximal to the confluence of the iliac veins, and the proximal end anastomosed to the lateral aspect of the superior mesenteric vein.144 Due to complications secondary to venous stasis, specifically intractable lower extremity edema, this shunt was never widely used in adults. Creation of the side-to-side mesocaval shunts begin with mobilization of the superior mesenteric vein and inferior vena cava such that they are parallel to one another. (Figure 11) These shunts are performed similarly to that of the side-to-side portacaval shunt discussed above. The final technique for creating a total mesocaval shunt uses either homologous vein graft or prosthetic grafts as a conduit from the superior mesenteric vein to the inferior vena cava.145,146 An advantage of mesocaval interposition shunts is that the shunt remains far from the porta hepatis and does not alter its anatomy so as not to compromise the technical aspects of a subsequent transplantation procedure. Kinking and thrombosis due to the length necessary to traverse the distance can prove to be

problematic in some cases however outcomes are similar to other total shunts.147 With diameters of 16-22 mm these shunts result in total shunting of portal flow.

Proximal Splenorenal Shunt The fourth totally diverting shunt we will describe is the proximal or central splenorenal shunt. This type of shunt is most often used in children with extrahepatic portal vein obstruction or those with portal hypertension and symptomatic splenomegaly/hypersplenism as it invariably includes splenectomy. 148,149 The splenic vein is taken close to the spleen and is then sutured to the left renal vein in a side-to-side, end-to-side, or end-to-end fashion. This creates a functional shunt through which all blood from the SMV and IMV is shunted into the caval system through the left renal vein. Post-shunt encephalopathy rates are similar to other total shunts however risk of thrombosis and variceal rebleeding are slightly higher. 149

Partially Diverting Shunts Partially diverting shunts, while still considered non-selective shunts since they are able to reduce portal pressure threshold to below 12 mmHg to reduce the risk of variceal bleeding, are only partially diverting, such that hepatopetal flow is maintained. 3 The two most common partially diverting shunts are smaller-diameter variations of aforementioned totally diverting shunts that often employ the use of synthetic graft material to prevent shunt dilation overtime. Variceal bleeding resolves in 80-90% of patients, and post-shunt encephalopathy occurs at less than

half the rate (21%) of totally diverting shunts.150 However, due to smaller diameters and increased resistance, shunt thrombosis occurs in up to 23% of cases. 150,151

Partial (Sarfeh) Portocaval Shunt The Sarfeh shunt is performed using an 8 to 10 mm PTFE H graft with a length from 3 to 5 cm that is sutured first to the anterior surface of the vena cava followed by anastomosis to the lateral aspect of the portal vein. (Figure 12) Sarfeh and colleagues worked to perfect this procedure finding the balance between reductions in portal pressures to alleviate the risk of variceal hemorrhage while maintaining prograde portal flow to minimize the incidence of encephalopathy. With a minimum diameter of 8 mm this partial shunt produces adequate decompression of mesenteric vessels to prevent variceal bleeding yet continues to maintain a relatively hypertensive portal system. Ligation and/or subsequent ablation of the coronary, umbilical, and gastroepipolic veins further reduce the risk for variceal hemorrhage. 150,152 Lastly, due to the relatively hypertensive portal system that remains, patients undergoing the Sarfeh procedure were more likely to have clinically limiting ascites despite diuretic therapy as compared to those patients undergoing total shunting procedures. 150

Interposition Mesocaval Shunt This small-diameter interposition shunt is a variation of the totally diverting sideto-side mesocaval shunt described above. The ability to create a partially diverting mesocaval shunt is based upon the diameter of the interposition graft used. Most

interposition mesocaval shunts have a diameter of 8 mm and a length of 5-8 cm. Several different graft materials have been utilized over its history including Dacron and internal jugular vein grafts. Currently the most commonly used grafts are made out of PTFE. The interposition graft is first sutured to the anterior aspect of the inferior vena cava followed by the superior mesenteric vein anastomosis. Care is taken to ensure appropriate length and positioning of the graft to avoid both kinking and tension. 145

Selective Surgical Shunts Selective shunts create two separate drainage systems achieving only partial decompression of the portal circulation. Successful selective shunts achieve reduced pressures in the esophagogastric system and higher pressures in the mesenteric system. Portal pressure and flow is maintained and the risk for postshunt encephalopathy is reduced to between 5 and 14%.153,154 Five-year survival approaches 80% and cessation of bleeding occurred in nearly 100% of patients. 148 Hepatic pressures remain elevated and these shunts are ineffective at reducing the burden of ascites. Indications for selective shunts include patients with variceal bleeding who have preserved liver function and in whom endoscopic and pharmacologic interventions have failed, for those patients in remote locations who need definitive control of their bleeding varices or those who are unlikely to be able to comply with the follow-up necessary after TIPS or endoscopic management.

Distal splenorenal (Warren) shunt The Warren shunt was introduced in 1967 by Warren et al. 155 gaining significant popularity until it became the most widely used operation for control of variceal bleeding worldwide. 139 The procedure begins with careful dissection of the splenic vein, exposing a segment starting close to the junction with the superior mesenteric vein and extending four to six centimeters distally. Care is taken to avoid avulsion of tributaries from the splenic vein during dissection. Attention is next turned to retroperitoneal dissection to isolate the left renal vein. The splenic vein is clamped and ligated at its junction with the inferior mesenteric vein and the proximal stump is oversewn. The distal end of the splenic vein is then anastomosed to the freed segment of the left renal vein. 155 (Figure 13) Following completion of the shunt procedure the splenocolic, gastrocolic, and gastrohepatic ligaments are divided with preservation of the gastropsplenic ligament. The left gastric artery and coronary vein are also identified and ligated. Esophagogastric varices are effectively decompressed through the stomach into the splenic vein, through the renal vein and into the caval system. Hepatopetal flow is maintained in the majority of patients and persists in 84 to 90% after 4 years. 153 Loss of prograde flow through the portal system can occur overtime due to portal vein thrombosis or increased flow through pancreatic collateral veins. This second complication can be prevented through splenopancreatic disconnection, involving complete dissection of the splenic vein from the posterior aspect of the pancreas.156 Control of hemorrhage approaches 90% and avoids dissection of the porta hepatis so as not to add complexity to a

subsequent transplant procedure. This shunt is contraindicated in patients with previous splenectomies and in those patients who have large-burden ascites.

Other Surgical Procedures for Decompression

Surgical Devasularization Esophageal devascularization as an alternative to shunting in patients with significant portal thrombosis and was introduced by Sugiura and Futagawa in 1973.157 The procedure, which later became known as the Sugiura operation, included esophageal transection with extensive paraesophagogastric devascularization, splenectomy, vagotomy and pyloroplasty via dual transthoracic and transabdominal incisions. Thoracic esophageal exposure is obtained via left lateral thoracotomy at the sixth intercostal space. Thoracic esophageal devascularization is performed from the diaphragmatic hiatus to the inferior pulmonary vein. Esophageal transection occurs at the level of the diaphragm and a two layer, hand sewn or stapled anastomosis is performed. The abdominal portion can be approached through a number of upper abdominal incisions. The devascularization is continued from the abdominal esophagus onto the greater and lesser curvature of the stomach. Splenectomy, vagotomy and pyloroplasty are performed.157,158 A number of modifications of this procedure are proposed including entirely transabdominal and vagus nerve sparing approaches.159,160 Esophageal rebleeding rates after devascularization vary from 0-37%.158,160

Comparative studies show the rates of recurrent bleeding following devascularization procedures has been higher than those achieved with operative shunting.161 Major complications include anastomotic leak (0-18%), esophageal stenosis (11-37%), and hepatic encephalopathy (0-11%).158 High operative mortality of over 20% is reported in the emergency setting and can be as high as 57100% in Child-Pugh class C cirrhotics.

Splenopneumopexy Traditional portosystemic shunting options are ineffective in patients who present with diffuse portal, splenic, and mesenteric flow due to an insufficient venous flow gradient. These patients may benefit from a splenopneumopexy, in which an anastomosis between the spleen and left inferior lobe of the lung establishes collateral blood flow and allows for portopulmonary shunting. (Figure 14) In the 1950s, surgeons in Finland were inspired by a wartime case of traumatic herniation of the spleen into the thoracic cavity in which portopulmonary shunting of blood developed via abundant collateral circulation between the spleen and lung. From this inspiration they went on to report three cases of thoracic transposition of the spleen in patients suffering from portal hypertension and bleeding esophageal varices.162,163 In each case, the patient recovered uneventfully and suffered no further hematemesis over a minimum two-year follow-up.162,163 This procedure appeared to reduce portal pressure in both hepatic and extrahepatic portal hypertension, with no deterioration in hepatic function.

In 1959, Walker and colleagues published an additional series of animal studies involving splenopneumopexy, confirming that the anastomosis was technically feasible, and that an excellent portopulmonary shunt existed within several days postoperatively.164 Subsequently, numerous manuscripts have been published reporting treatment of portal hypertension of both hepatic and extrahepatic etiology with splenopneumopexy.165-170

As with all major procedures, proper patient selection is crucial for achieving optimal outcomes. Though most published reports discuss splenopneumopexy in the setting of Budd Chiari Syndrome, we have performed the procedure for an additional indication: diffuse portal, splenic, and mesenteric thrombosis.165,166,168 Due to the significant visceral occlusion, and subsequent lack of a venous flow gradient, these patients typically are not candidates for traditional shunting procedures such as spleno-renal shunting, spleno-portal shunting, or TIPS.171 Additionally, the resulting splenomegaly developed secondary to diffuse visceral thrombosis and subsequent venous congestion provides significant splenic enlargement sufficient to create an adequate anastomosis with the lung. Due to the minimal intraperitoneal exposure, splenopneumopexy is also advantageous for patients with portal hypertension who present with significant intra-abdominal adhesions from prior operations in which alternative extensive operations may prove difficult. Similarly, splenopneumopexy has also been successfully described in

patients who have previously failed less invasive therapeutic interventions.167 In addition, this operation still allows for further decompressive procedures to be performed without added difficulty as in this procedure the abdomen is not violated in this procedure.

Postoperatively, patients undergoing splenopneumopexy develop extensive blood flow between the portal venous and pulmonary venous systems. In addition to this portopulmonary shunting, extensive collateral flow may develop within the intercostal, phrenic, pericardiophrenic, or mediastinal veins. (Figure 15) Evaluation of blood flow via systemic computerized tomography (CT) venography or splenoportography demonstrates significant collateral spleno-pneumo-atrial blood flow.172 This cumulative collateral flow results in significant regression, if not complete resolution, of esophagogastric varices in most patients.167

Surgeons at our institution have performed splenopneumopexy on five patients over a fifteen-year period. Each patient presented with complete venous occlusion of at least two of the three major visceral venous systems, resulting in significant and ongoing gastrointestinal hemorrhage from esophageal and/or gastric varices. For patients in whom the splenopenumopexy proved successful, no patients required a blood transfusion following the procedure and none of these patients have required further intervention for their variceal bleeding at most recent followup.173 This finding is consistent with other series within the limited literature, which

report success rates of 65-100% in patients who undergo splenopneumopexy for various indications. 165,167,168 Additionally, when this procedure is typically performed on patients with normal preoperative liver function, the rates of hepatic dysfunction or hepatic encephalopathy are extremely low.167

While this procedure appears successful in a large number of well-selected patients, it does not always prove efficacious. Despite radiographic evidence of some collateral circulation and potential regression of varices, reports suggest shunting failure and a potential for re-bleeding in up to one-third of patients.167 One patient in our series continued to experience ongoing blood loss requiring intermittent blood transfusions. For this patient and many others, splenopneumopexy may be considered a temporizing measure to more invasive procedures such as the Suguria procedure.

Liver Transplantation The majority of patients who manifest portal hypertension by variceal bleeding have ESLD. Therapy with liver transplantation offers the most definitive corrective therapy if they are a transplant candidate. Patients with well compensated liver disease and even ESLD may be appropriately treated with TIPS, surgical shunts, or medical therapy first and in the acute setting as a temporizing measure. Despite the shortage of donor organs and morbidity and mortality associated with liver transplantation, its use in the semi-urgent setting is appropriate if the proper

workup for transplant is performed. Patients with contraindications to transplant such as severe pulmonary hypertension, acute alcoholic hepatitis, or psychosocial barriers will require alternative therapies.174 These therapies can be used as a bridge as the workup for liver transplant is performed. In the presence of portal hypertension that is severe, temporizing measures can lead to decompensation requiring urgent liver transplantation, which is why it is important to pursue workup in a timely fashion. If a surgical shunt or some type of surgical procedure is performed as a temporizing measure, we advocate earlier transplant before scar and other adhesive tissue has developed.

Conclusions Development of varices due to portal hypertension is a common and often lifethreatening occurrence in patients with cirrhosis. Primary prophylaxis is critical in this patient population due to the mortality rate associated with variceal rupture. When prophylactic treatments fail, endoscopic and endovascular interventions allow for reliable, non-invasive means of hemorrhagic control. Surgical decompression provides excellent hemorrhage control and is reserved for recurrent bleeding or for patients unable to comply with the follow-up needed following endoscopic interventions or TIPS due to the complications associated with surgical shunt procedures. Liver transplantation provides the most definitive therapy for appropriate candidates with bleeding varices due to cirrhosis.

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Figure Legends Figure 1. Cirrhosis of the liver. Figure 2. Endoscopic image of an esophageal varix in a patient with cirrhosis and portal hypertension. Figure 3. Management algorithm for the cirrhotic patient with an acute episode of upper GI bleeding. Figure 4. Picture of a patient with a Blakemore tube in place for the treatment of acutely bleeding esophageal varices. Figure 5. Endoscopic image of an esophageal varix post banding. Figure 6: balloon-occluded retrograde transvenous obliteration (BRTO) imaging demonstrating gastroesophageal varices selected in a retrograde fashion from the left renal vein via a gastro/splenorenal shunt. Figure 7: Ablation and coil embolization performed under fluoroscopic guidance. Figure 8. Transjugular intrahepatic portosystemic shunt. Figure 9: Neointimal hyperplasia of TIPS graft. Figure 10. Side-to-side portocaval shunt Figure 11: Side-to-side mesocaval shunt

Figure 12: Partial portocaval shunt using PTFE H graft. Figure 13: Distal splenorenal shunt Figure 14: CT image demonstrating anatomic juxtapositioning of the spleen to the left lower lobe after splenopneumopexy Figure 15: Demonstration of extensive collateral flow within the intercostal, phrenic, pericardiophrenic, and mediastinal veins following splenopneumopexy.

Tables Table 1: Causes of portal hypertension Category Causes Presinusoidal

Schistosomiasis Portal vein thrombosis Umbilical vein thrombosis Malignancy Congenital hepatic fibrosis Primary biliary cirrhosis

Sinusoidal

Cirrhosis

Postsinusoidal

Budd-Chiari syndrome Inferior vena cava webs Malignancy Congestive heart failure Restrictive pericarditis

Table 2: Predicting mortality in end-stage liver disease Scoring system Endpoint(s) Variables measured Child-Pugh-Turcotte 1-year and 2classification year mortality

Albumin Bilirubin INR Hepatic encephalopathy Ascites

Model for end-stage liver disease (MELD) score

90-day mortality

Bilirubin INR Creatinine (with exception for dialysis)

Table 3: Etiology of gastrointestinal hemorrhage in cirrhotics Causes Causes related to portal hypertension

Esophageal varices (>60%) Gastric varices (5-10%) Portal hypertensive gastropathy (2-10%) Ectopic varices (1-5%)

Causes independent of portal hypertension

Mallory-Weiss syndrome Malignancy Peptic ulcer disease Erosive gastritis Reflux esophagitis Dieulafoy lesion

Biographical Information

Audrey E. Ertel MD, MS Audrey Ertel is currently a fourth year surgical resident at the University of Cincinnati Medical Center. Her medical school training was completed at Thomas Jefferson Medical College in Philadelphia and she completed a Master’s degree in Clinical and Translational Research at the University of Cincinnati Medical College during her first year of research fellowship. She is currently in her second year of research and focuses primarily on health services and outcomes research with the Cincinnati Research on Outcomes and Safety in Surgery (CROSS) group.

Alex Chang, MD Alex Chang completed a biomedical engineering bachelors at the University of Texas and a medical degree at Baylor College of Medicine. He is currently a resident in general surgery at the University of Cincinnati Medical Center. Dr. Chang is completing a 2-year research fellowship focusing on the immune response to blood transfusion in animal models and he is pursuing a fellowship in transplantation.

Young Kim, MD, MS Young Kim is a Resident in the Department of Surgery at the University of Cincinnati Medical Center. After obtaining a Master’s degree in Cellular Biology at the University of Michigan, he graduated from medical school the University of Cincinnati and continued his training in General Surgery at the same institution. He is currently completing a research fellowship in the study of aged blood and its deleterious effects on the hemorrhaging patient. After the completion of his general surgery residency he is interested in pursuing a fellowship in transplantation.

Shimul A. Shah, MD, MCMH Shimul Shah is the Director of Liver Transplantation and Hepatobiliary Surgery with a special interest in health services research at the University of Cincinnati School of Medicine. He has a very busy clinical practice in liver, kidney and pancreas transplantation, and hepatobiliary surgery. He specializes in the care of patients with end-stage liver disease, colorectal cancer metastases, and hepatocellular carcinoma. He has made contributions to our understanding and management of liver transplantation and hepatobiliary surgery, volume and outcomes in surgery, and investigating under-utilization and disparities in surgical and cancer care. At Cincinnati, he has started and directed Cincinnati Research in Outcomes and Safety in Surgery (CROSS), a multidisciplinary group focused on health services research.

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