Portal Hypertension Treatment & Management

Treatment is directed at the cause of portal hypertension. Gastroesophageal variceal hemorrhage is the most dramatic and lethal complication of portal hypertension; therefore, most of the following discussion focuses on the treatment of variceal hemorrhage. Medical care includes emergent treatment, primary and secondary prophylaxis, and surgical intervention.

Pharmacologic therapy for portal hypertension includes the use of beta-blockers, most commonly propranolol and nadolol. Brazilian investigators have suggested that the use of some statins (eg, simvastatin) may lower portal pressure and potentially improve the liver function. ^[34] In a 3-month prospective, triple-blind randomized trial with simvastatin 40 mg/day and placebo in 34 patients with cirrhotic portal hypertension, 55% of those who received simvastatin showed a clinically relevant decrease in hepatic venous pressure gradient compared to none in the placebo group. Moreover, simvastatin response rates were greater in those with medium to large esophageal varices and previous variceal bleeding. ^[34]

Endoscopic procedures such as sclerotherapy and variceal ligation can be used to prevent the recurrence of variceal hemorrhage. Surgical care includes the use of decompressive shunts, devascularization procedures, and liver transplantation. Decompressive shunts and devascularization procedures are mainly rescue therapies.

Management of patients with liver cirrhosis and ascites but without variceal hemorrhage includes a low-sodium diet and diuretics.

Nasogastric tube

In patients with hemodynamically significant upper gastrointestinal (GI) tract bleeding, a nasogastric tube should remain in place for 24 hours to assist in identifying any rebleeding. Gastric lavage may be performed frequently through the nasogastric tube, and the volume and appearance of material aspirated from the stomach should be recorded. Do not allow any food by mouth.

Transfer

Initial volume resuscitation with or without blood product transfusion, together with medical treatment to reduce portal pressure (ie, anti-secretory agent infusion) should be promptly initiated in the emergency department. A transfer may be necessary if endoscopic treatment and/or surgical treatment are not readily available. If possible, transfer patients with uncontrollable bleeding from portal hypertension; these individuals should be sent to a tertiary center with a liver transplantation service.

Surgery has no role in primary prophylaxis. Its role in acute variceal bleeding is exceedingly limited, because therapy with endoscopic treatment controls bleeding in 90% of patients. A transjugular intrahepatic portosystemic shunt (TIPS) is a viable option and is less invasive for patients whose bleeding is not controlled. However, if TIPS is not available, then staple transection of the esophagus is an option when endoscopic treatment and pharmacologic therapy have failed.

Consider surgery for the prevention of rebleeding when pharmacologic and/or endoscopic therapy have failed. As per the Baveno II consensus conference on portal hypertension, failure is defined as a single episode of clinically significant rebleeding (transfusion requirement of 2 U of blood or more within 24 h, a systolic blood pressure < 100 mm Hg or a postural change of >20 mm Hg, and/or a pulse rate greater than 100 bpm). ^[35]

Surgical interventions include the following:

• Portosystemic shunts

• Devascularization procedures

• Orthotopic liver transplantation (OLT) - Treatment of choice in patients with advanced liver disease

Surgical shunts provide better control of rebleeding when compared to the combination therapy of beta-blocker and endoscopic variceal ligation (EVL). However, these shunts are associated with higher incidence of hepatic encephalopathy and should be reserved for Child class A patients with recurrent bleeding despite adequate combination therapy. Decompressive shunts include total portal systemic shunts, partial portal systemic shunts, and other selective shunts.

Total portal systemic shunts

Total portal systemic shunts include any shunt larger than 10 mm in diameter between the portal vein (or one of its main tributaries) and the inferior vena cava (IVC) (or one of its tributaries).

Eck fistula (a classic end-to-side portacaval shunt; described for historical interest only) was performed by Eck in dogs in the late 19th century. The portal vein is divided close to the liver, the hepatic end of the portal vein is ligated, and the splanchnic end is anastomosed to the IVC. This controls variceal bleeding and decompresses splanchnic hypertension but leaves high pressure in the hepatic sinusoids; thus ascites is not relieved.

For the side-to-side portacaval shunt, the portal vein and the infrahepatic IVC are mobilized after dissection and anastomosed. All portal flow is directed through the shunt, with the portal vein itself acting as an outflow from the obstructed hepatic sinusoids. Excellent control of bleeding and ascites is achieved in more than 90% of patients. Encephalopathy (rate of 40-50%) and progressive liver failure are possible. The procedure has relatively limited indications, which include massive variceal bleeding with ascites or acute Budd-Chiari syndrome without evidence of liver failure.

Partial portal systemic shunts

Partial portal systemic shunts reduce the size of the anastomosis of a side-to-side shunt to 8 mm in diameter. Portal pressure is reduced to 12 mm Hg, and portal flow is maintained in 80% of patients.

The operative approach is similar to that for side-to-side portacaval shunts, except the interposition graft must be placed between the portal vein and the IVC.

Two prospective, randomized, controlled trials revealed a 90% rate for control of bleeding. Maintenance of some portal flow has decreased the incidence of encephalopathy and liver failure.

Selective shunts

Selective shunts provide selective decompression of gastroesophageal varices to control bleeding while at the same time maintaining portal hypertension to maintain portal flow to the liver. One example is the distal splenorenal shunt, which is the most commonly used decompressive operation for refractory variceal bleeding; it is used primarily in patients who present with refractory bleeding and continue to have good liver function. The distal splenorenal shunt decompresses the gastroesophageal varices through the short gastric veins, the spleen, and the splenic vein to the left renal vein.

Portal hypertension is maintained in the splanchnic and portal venous system, and the shunt maintains portal flow to the liver. This type of shunt provides the best long-term maintenance of some portal flow and liver function, with a lower incidence of encephalopathy (10-15%) compared with total shunts. The operation produces ascites because the retroperitoneal lymphatics are diverted.

Devascularization is rarely performed but may have a role in patients with portal and splenic vein thrombosis who are not suitable candidates for shunt procedures and who continue to have variceal bleeding despite endoscopic and pharmacologic treatment.

Devascularization procedures consist of the transabdominal devascularization of the lower 5 cm of the esophagus and the upper two thirds of the stomach, with staple gun transection of the lower esophagus) (eg, splenectomy, gastroesophageal devascularization, and esophageal transection [at times]).

The incidence of liver failure and encephalopathy is low following devascularization procedures, presumably because of better maintenance of portal flow. However, these procedures are rarely performed but may have a role in patients with portal and splenic vein thrombosis who are not suitable candidates for shunt procedures and who continue to have variceal bleeding despite endoscopic and pharmacologic treatment.

Splenectomy

The spleen is one of the major inflow paths to gastroesophageal varices. ^[36] Splenectomy allows better access to the gastric fundus and the distal esophagus to complete the devascularization.

Portal vein thrombosis of as much as 20% is reported following splenectomy. Ascites is a frequent early postoperative complication because the portal hypertension is maintained.

Gastroesophageal devascularization (Sugiura procedure)

Gastroesophageal devascularization should devascularize the whole greater curve of the stomach from the pylorus to the esophagus and the upper two thirds of the lesser curve of the stomach. The esophagus should be devascularized for a minimum of 7 cm.

In patients who have undergone extensive and repeated sclerotherapy, the gastroesophageal junction is thickened and the ability to perform a satisfactory transection is limited.

Liver transplantation should be considered for patients with end-stage liver disease (eg, cirrhotic patients with Child-Pugh score =7 or Model for End-Stage Liver Disease [MELD] score =15 [see the MELD Score calculator]). ^[8] The selection of candidates is dictated by the patient's clinical status, etiology of cirrhosis (viral hepatitis, alcoholic, nonalcoholic steatohepatitis, cholestatic liver disease), abstinence from alcohol, and availability of a donor organ.

Liver transplantation is the ultimate shunt, because it relieves portal hypertension, prevents variceal rebleeding, and manages ascites and encephalopathy by restoring liver function. It is the treatment modality that has significantly improved the outcome of patients with Child-Pugh class C disease and variceal bleeding. ^[37]

In most patients, it is impractical to use liver transplantation to treat portal hypertension, because these individuals can be managed successfully with lesser methods. Therefore, the use of transplantation must be based on appropriate patient selections, as follows ^[38] :

• For patients with Child class A disease, shunt surgery is recommended

• For patients with Child class B disease, shunt surgery or a transjugular intrahepatic portosystemic shunt (TIPS) is appropriate

• For people with Child C class disease, TIPS or OLT is recommended

A study by Burger-Klepp et al indicated that, despite concerns that transesophageal echocardiography (TEE) can cause esophageal and gastric variceal hemorrhage, TEE is a relatively safe means of monitoring cardiac performance in patients with varices who are undergoing OLT. Of 287 patients in the study who underwent OLT and who had esophageal (82.2%), gastric (4.2%), or esophagogastric (13.6%) varices, only 1 major incidence of hemorrhage occurred. ^[37]

Secondary prophylaxis is used to prevent rebleeding. Variceal hemorrhage has a 2-year recurrence rate of approximately 80%.

Nonselective beta-blockers

Propranolol and nadolol significantly reduce the risk of rebleeding and are associated with prolongation of survival. Studies comparing propranolol with sclerotherapy in the prevention of variceal rebleeding demonstrated comparable rates of variceal rebleeding and survival, but sclerotherapy was associated with significantly more complications.

Endoscopic sclerotherapy

Endoscopic sclerotherapy is usually performed at weekly intervals. Approximately 4-5 sessions are required for the eradication of varices, which is achieved in nearly 70% of patients.

Endoscopic variceal ligation

Endoscopic variceal ligation (EVL) is considered the endoscopic treatment of choice in the prevention of rebleeding. Sessions are repeated at 7- to 14-day intervals until variceal obliteration (which usually requires 2-4 sessions). This procedure is associated with lower rebleeding rates and a lower frequency of esophageal strictures. Fewer sessions are required to achieve variceal obliteration than are required for sclerotherapy. See the video below.

Combination of EVL and pharmacologic therapy

A randomized trials demonstrated that EVL plus nadolol plus sucralfate is more effective in preventing variceal rebleeding than is EVL alone. ^[39] In a more recent study by the same investigators, combined EVL and pharmacotherapy was marginally more effective than pharmacotherapy alone for preventing variceal rebleeding. ^[40] These studies appear to indicate that combining EVL with beta-blockers is reasonable for patients in whom pharmacologic therapy has failed.

However, another report had different results. In a study by Kumar et al that compared the effectiveness of EVL alone with that of combination therapy consisting of EVL, propranolol, and isosorbide mononitrate (ISMN) for secondary prophylaxis in patients with previous variceal bleeding, no difference between the groups was observed for rebleeding 2 years after initial therapy. ^[41] The investigators concluded that EVL by itself is sufficient to prevent variceal rebleeding. Moreover, they found that the addition of propranolol and ISMN to EVL may increase the risk for adverse effects. ^[41]

Despite the contrasting findings above, combination of beta-blocker therapy with EVL is considered to the best option for secondary prophylaxis of variceal hemorrhage. Rather than titrating beta-blockers to goal reduction in heart rate, doses should be titrated to the maximal tolerated dose, because a goal reduction in heart rate may not correlate to a reduction in hepatic venous pressure gradient (HVPG). EVL should be repeated every 1-2 weeks until complete variceal obliteration occurs; then, endoscopy can be repeated every 3-6 months to evaluate for recurrence and for the need to repeat EVL. ^[8] .

Complications of EVL are not frequent (14%) and usually minor, including transient dysphagia, chest discomfort, and small ulcer around the variceal base. Treatment with a proton-pump inhibitor for 10 days after EVL can reduce the size of these ulcers. ^[8]

Complications related to the therapeutic procedures used in management of bleeding esophageal varices include the following:

• Balloon tamponade - Aspiration pneumonia, esophageal perforation, superficial lesions of the gastric mucosa, and pressure necrosis of the nasal passages, mouth, or lips

• Sclerotherapy - Perforation of the esophagus (2-6%), esophageal ulceration and bleeding (2-13%), pleural effusion (16-48%), fever (30%), chest pain (40%), and esophageal stricture (7%)

• Variceal banding - Rebleeding during the course of banding

• Surgical procedures - For example, distal splenorenal shunt surgery is associated with an increased incidence of hepatic encephalopathy.

• Liver transplantation - Rejection, infection, sepsis, and complications related to immunosuppressive drugs used postoperatively

• Complications related to pharmacotherapy

• Complications related to blood transfusion

Consider early consultation with a gastroenterologist and a surgeon, particularly for patients with active bleeding from esophageal varices. Consultation with a hepatologist and transplant surgery should be considered in patients with Child class B or C disease or a high Model for End-Stage Liver Disease (MELD) score. Good coordination among gastroenterologists, interventional radiologists, critical care team, and surgeons is essential.

To prevent recurrent variceal hemorrhage, patients with portal hypertension should have endoscopic variceal ligation (EVL) sessions scheduled until complete obliteration of varices is achieved. EVL sessions are repeated at 7- to 14-day intervals. These usually require 2-4 sessions for complete obliteration of varices.

As noted in Upper Gastrointestinal Endoscopy, periodic surveillance endoscopy should be performed in patients with cirrhosis as follows ^{[8, 12, 19]} :

• Repeat endoscopy annually in decompensated patients, patients with alcohol abuse, and patients with stigmata of variceal bleeding

• Repeat endoscopy at 1-2 years to evaluate the progression of varices in compensated patients with small varices

• Repeat endoscopy at 2-3 years to evaluate for the development of varices in compensated patients without varices

Ferreira et al suggested that a high portal blood flow velocity can indicate progression of gastroesophageal varices and the need to include the patient in a postoperative, on-demand, endoscopic follow-up program of varices eradication (rather than in a prophylactic program). ^[36] Their study findings included significantly higher values of portal blood flow velocity in patients with variceal progression. Those with a portal flow velocity of greater than 15.5 cm/s at the first postoperative year not only had progression of gastroesophageal varices but also were at higher risk for rebleeding. ^[36]

These investigators analyzed data on portal vein Doppler ultrasonography for postoperative follow-up in 146 patients with schistosomal portal hypertension and a previous history of upper digestive bleeding from gastroesophageal varices rupture, who had undergone a gastroesophageal devascularization procedure with splenectomy. ^[36] At each of 4 postoperative time points—1, 2, and 5 years and up to 10 years—patients were separated into 2 groups according to gastroesophageal varices progression; diameter and mean blood flow velocity were measured at these time points. ^[36]

Promptly resuscitate and restore the circulating blood volume in patients with suspected cirrhosis and variceal hemorrhage (bleeding esophageal varices can be fatal). Rapid initial evaluation with measurement of vital signs, including orthostatic hypotension, assessment of the rate and volume of bleeding, mental status, and patient's ability to protect the airway is mandatory.

Establish 2 large-bore venous accesses for blood transfusion. While results are pending for the complete blood count (CBC), prothrombin/partial thromboplastin time (PT/PTT), and international normalized ratio (INR) and while the blood is being cross-matched, start rapid infusion of 5% dextrose and colloid solution until the blood pressure is restored and the urine output is adequate. Obtain other laboratory tests (eg, serum electrolyte levels, including calcium, especially when a large transfusion is required; serum creatinine levels; and liver function tests [LFTs]) (see Laboratory Studies).

Blood should be replaced at a modest target of the hematocrit of 25-30%. The goal is to maintain hemodynamic stability and hemoglobin of approximately 8 g/dL. ^{[8, 42, 43]} As soon as the acute bleeding episode is adequately controlled, it is critical to initiate therapy to prevent recurrent bleeding. Fluid resuscitation should be made with caution: Avoid vigorous saline and blood infusion due to the risk of rebound increased portal pressure precipitating recurrent variceal hemorrhage and ascetic fluid accumulation. If indicated (eg, patients with severe coagulopathy with/without significant thrombocytopenia [< 50,000/mm³ platelets]), correct clotting factor deficiencies with fresh frozen plasma, fresh blood, and vitamin K.

Establish airway protection in patients with massive upper gastrointestinal (GI) tract bleeding, especially if the patient is not fully conscious.

Insert a nasogastric tube to assess the severity of the bleeding, to decompress the stomach, and to lavage the gastric contents to improve visualization during endoscopy.

Bleeding from esophageal varices

Variceal bleeding may cease spontaneously in as many as 50% of patients. ^[15] Each episode of variceal bleeding is associated with a 30% mortality rate. Such episodes occur mostly in patients with severe liver disease and in those with early rebleeding. Rebleeding occurs in 40% of patients within 6 weeks. ^[44]

Following resuscitation, treatment of acute variceal bleeding includes control of bleeding (24 h without bleeding within the first 48 h following the start of therapy) and prevention of early recurrence.

Prevention of complications

All patients with cirrhosis and upper GI bleeding are at a high risk for developing severe bacterial infections. These infections are associated with early rebleeding.

A short course of prophylactic antibiotics has been demonstrated to decrease both the rate of bacterial infections and mortality rates. The improvement in the survival rate with antibiotic prophylaxis has been attributed to a decrease in early rebleeding. ^{[8, 15]} Thus, prophylactic antibiotic use (norfloxacin 400 mg PO bid for 7 d; alternatively, PO ciprofloxacin or other broad-spectrum antibiotics) in the setting of acute bleeding is recommended, including cirrhotic patients with upper GI bleeding with/without ascites. ^{[8, 45]} If oral administration is not possible, intravenous (IV) ciprofloxacin may be used. IV ceftriaxone should be considered in patients with advanced cirrhosis and in centers with documented quinolone-resistant bacteria. ^{[8, 46]}

Combination endoscopic and pharmacologic therapy minimizes the risk of complications, especially within the period when the risk of rebleeding is the greatest (ie, within 5 days of initial episode).

Beta-blocker therapy is not recommended in the setting of acute bleeding owing to its potential to cause hypotension, further diminishing the compensatory tachycardia to hemorrhage. ^[8]

Vasoconstrictors

Somatostatin (not available in the United States) is an endogenous hormone that at pharmacologic doses decreases portal blood flow by splanchnic vasoconstriction, without significant systemic adverse effects.

Octreotide

Octreotide is the pharmacologic agent of choice in acute variceal bleeding and is used in conjunction with endoscopic therapy. ^{[15, 47, 48]} This agent is a synthetic analogue of somatostatin that is usually administered at a constant infusion of 50 mcg/h. Octreotide has been shown not only to be effective in reducing the complications of variceal bleeding after emergency sclerotherapy or variceal ligation, but it is also superior to vasopressin, particularly in its side effect profile.

Vasopressin

Vasopressin is the most potent splanchnic vasoconstrictor; it reduces blood flow to all splanchnic organs, decreasing portal venous inflow and portal pressure. This agent should not be administered via a central line, especially in elderly patients or patients with coronary artery disease, because of possible coronary vasospasm and subsequent myocardial infarction (MI). Use of vasopressin is also limited by adverse effects related to splanchnic vasoconstriction (eg, bowel ischemia) and systemic vasoconstriction (eg, hypertension, myocardial ischemia). Continuous infusion of 0.2-0.4 IU/min (not to exceed 0.8 IU/min) is recommended.

Vasopressin always should be accompanied by intravenous nitroglycerin at a dose of 40 mcg/min (not to exceed 400 mcg/min) to maintain a systolic blood pressure of greater than 90 mm Hg. Adding nitrates to vasopressin therapy significantly improves efficacy, although the adverse effects of combination therapy are higher than those associated with terlipressin or somatostatin.

Terlipressin

Terlipressin (not approved by the US Food and Drug Administration [FDA] for use in the United States) is a synthetic analogue of vasopressin that has longer biologic activity and significantly fewer adverse effects than vasopressin. Therapy should be continued for up to 5 days following the initial variceal hemorrhage to reduce the risk of recurrent bleeding.

A randomized, controlled trial showed that octreotide only transiently reduced portal pressure and flow, whereas the effects of terlipressin were sustained. ^[49] These findings suggest that terlipressin may have more sustained hemodynamic effects in patients with bleeding varices. ^[49]

Vasoactive drugs are safe and effective alternative therapy whenever endoscopic ligation (banding) therapy is not promptly available. ^[50] In addition, pharmacotherapy seemed to create less adverse events than emergency sclerotherapy. ^[50]

Endoscopic therapy

Perform endoscopy as soon as possible after the patient has been resuscitated. ^[51] The aim is to establish the cause of and to control the bleeding, and endoscopic therapy has the advantage of allowing specific treatment to be provided at the time of diagnosis. This procedure has largely replaced balloon tamponade as the initial nonpharmacologic hemostatic modality for variceal bleeding.

Efficacy in achieving hemostasis is higher than 80% with endoscopic therapy, but its effectiveness declines to 70% at day 5 due to very early rebleeding in some patients. Failures in endoscopic treatment may be managed with a second session of such therapy, but no more than 2 sessions should be allowed before deciding to perform a transjugular intrahepatic portosystemic shunt (TIPS) procedure or surgery.

Endoscopic variceal ligation

EVL is the preferred endoscopic therapy in acute esophageal variceal bleeding. ^{[8, 15]} It has superiority over sclerotherapy in all major outcomes (recurrent bleeding, local complications including ulceration and stricture formation, time to variceal obliteration, and survival).

This procedure is based on the widely used technique of rubber-band ligation of hemorrhoids. EVL is performed using a banding device attached to the tip of the endoscope. The varix is aspirated into the banding chamber, and a trip wire dislodges a rubber band carried on the banding chamber, ligating the entrapped varix. One to 3 bands are applied to each varix, resulting in thrombosis. Ultimately, strangulation, sloughing, and fibrosis obliterate the varices.

EVL and sclerotherapy have achieved similar rates of initial hemostasis in patients whose varices were actively bleeding at the time of treatment. However, a meta-analysis of 10 randomized controlled trials patients showed an almost statistically significant benefit of EVL in the initial control of bleeding relative to sclerotherapy. ^[52] Moreover, EVL requires fewer treatment sessions than does sclerotherapy, and local complications are less common with EVL than with sclerotherapy. For example, esophageal strictures have been found to be less common with EVL than with sclerotherapy, and rebleeding has occurred less frequently with the ligation technique (26%) than with sclerotherapy (45%).

Systemic complications, however, such as pulmonary infections and bacterial peritonitis, have not been found to be significantly different between the 2 techniques. (However, a trend toward a decrease in these 2 complications in patients treated with ligation has been observed.) Moreover, there is no overall survival benefit to EVL over injection sclerotherapy.

A limitation of endoscopic ligation is that it requires placement of an opaque cylinder over the end of the endoscope, which decreases the endoscopic field of view and may allow pooling of blood. Thus, in patients with active bleeding, visualization may be impaired more with ligation than with sclerotherapy. In addition, EVL has the same limitations as injection sclerotherapy regarding availability, cost, and difficulty in treating gastric varices.

Although ligation has come to be considered the treatment of choice for esophageal varices, the choice of technique should hinge on the experience of the operator, as well as the particular circumstances found during endoscopic therapy.

Endoscopic injection sclerotherapy

Endoscopic injection sclerotherapy is a very effective emergency treatment for acute variceal bleeding (but it is not optimal for patients bleeding from gastric fundal varices). ^{[8, 42]} This procedure is an alternative procedure when EVL is not technically feasible, but sclerotherapy has higher complication rates relative to EVL. ^[12]

Treatment involves injecting a sclerosant solution into the bleeding varix, obliterating the lumen by thrombosis, or into the overlying submucosa, producing inflammation followed by fibrosis. Several different sclerosants are available, including 5% sodium morrhuate, 1-3% sodium tetradecyl sulfate, and 5% ethanolamine oleate. The typical volume used per injection is 1-2 mL of sclerosant, with the total volume ranging from 10 to 15 mL.

Hemorrhagic control should be obtained with 1-2 sessions. Patients continuing to bleed after 2 sessions should be considered for alternative methods to control their bleeding. Note that HVPG remains elevated 5 days following sclerotherapy, whereas it returns to baseline 48 hours following endoscopic variceal ligation (EVL). ^{[42, 53]}

In the United States, sodium tetradecyl sulfate or sodium morrhuate has generally been used as a sclerosant, whereas polidocanol or ethanolamine has been more popular in Europe. Variations in the technique or the sclerosant used have not been shown to influence the outcome.

Complications of endoscopic injection sclerotherapy, which are more frequent in acute bleeding than in elective situations, are related to the toxicity of the sclerosant and include transient fever, esophageal stricture formation, dysphagia, esophageal perforation (rarely), chest pain, mediastinitis, mucosal ulceration, and pleural effusion. ^{[8, 15]} Serious complications related to sclerotherapy have been reported in 15-20% of patients.

Balloon-tube tamponade

Approximately 5-10% of patients with esophageal variceal hemorrhage have conditions that cannot be controlled by endoscopic and/or pharmacologic treatment. Balloon tamponade (eg, Minnesota tube, Sengstaken-Blakemore [S-B] tube, Linton-Nachlas tube) may be used in the management of these patients; it achieves hemostasis in 60-90% of variceal bleedings.

However, this technique should be employed only in patients with massive bleeding and should serve only as a temporizing measure (should be used for < 24 h owing to the risk of esophageal rupture/necrosis) (ie, bridging therapy) until definitive treatment (eg, TIPS, surgical intervention) can be instituted.

Moreover, balloon-tube tamponade must be performed by experienced personnel because the procedure is potentially dangerous. An endotracheal tube should be placed to protect the airway before attempting to place the balloon tube.

Complications of balloon-tube tamponade are esophageal and gastric ulceration, aspiration pneumonia, and esophageal perforation. Continued bleeding during balloon tamponade indicates an incorrectly positioned tube or bleeding from another source.

The Minnesota tube is an adaptation of the S-B tube, the difference being that the S-B tube does not have an esophageal suction port to prevent aspiration. The Minnesota tube has 4 lumens, including 1 for gastric aspiration, 2 to inflate the gastric and esophageal balloons, and 1 above the esophageal balloon to suction secretions in order to prevent aspiration. The tube is inserted through the mouth, and its position within the stomach is checked by auscultation while air is injected through the gastric lumen.

The gastric balloon is inflated with 200 mL of air. Once fully inflated, the gastric balloon is pulled up against the gastroesophageal junction, using approximately 0.5 kg of traction, compressing the submucosal varices. The esophageal balloon rarely is required.

Percutaneous transhepatic embolization

Percutaneous transhepatic embolization (PTE) of gastroesophageal varices involves catheterization of the gastric collaterals that supply blood to varices via the transhepatic route. A variety of agents have been used, with varying degrees of success in controlling acute bleeding.

Generally, PTE is less effective than endoscopic sclerotherapy for the treatment of variceal hemorrhage, and it is much less effective compared with medical and surgical options. Thus, PTE should be reserved for situations in which acute variceal bleeding is not controlled by pharmaceutical treatment, endoscopic sclerotherapy, or endoscopic variceal ligation and in which contraindications for surgical management are present.

Cyanoacrylate monomer

Endoscopic administration of cyanoacrylate monomer (superglue) in gastric varices is another intervention. The occurrence of complications after gastric variceal obliteration with butyl cyanoacrylate is low, with a complication-related mortality rate of 0.53%. ^[54]

Transjugular intrahepatic portosystemic shunt

TIPS is a useful procedure for patients in whom bleeding has continued despite medical and endoscopic treatment, for patients with Child class C disease, and for selected patients with Child class B disease. It is effective only in portal hypertension of hepatic origin.

Under local anesthesia, with sedation via the internal jugular vein, the hepatic vein is cannulated and a tract is created through the liver parenchyma, from the hepatic to the portal vein, with a needle. This is performed under ultrasonographic and fluoroscopic guidance. The tract is dilated, and an expandable metal stent is introduced, connecting the hepatic and portal systems. Blood from the hypertensive portal vein and sinusoidal bed is shunted to the hepatic vein.

An international, multicenter study revealed that patients who received a TIPS early (within 72 h of presentation) had a significantly better chance of remaining free from bleeding than did patients who received standard care (fluid resuscitation, antibiotic prophylaxis, vasoactive drugs, early endoscopy with ligation, or sclerosis of varices). ^[55]

Indications

Accepted indications for a TIPS procedure (in which the efficacy of TIPS has been established in controlled trials) include: (1) active variceal bleeding despite emergency endoscopic and/or pharmacologic treatment and (2) recurrent variceal bleeding despite adequate endoscopic treatment.

Potential indications (in which the efficacy of the TIPS procedure has been proven but has not been adequately compared with that of existing therapies) include: (1) isolated bleeding from gastric fundic varices and (2) refractory ascites.

Experimental indications (in which efficacy has not been established in large-scale trials) include the following:

• Bleeding portal gastropathy

• Budd-Chiari syndrome

• Veno-occlusive disease

• Hepatorenal syndrome

• Hepatic hydrothorax

• Bleeding ectopic varices

• Protein-losing enteropathy due to portal hypertension

Recurrence of portal hypertension

Causes of recurrent portal hypertension and bleeding after a TIPS procedure include the following:

• Continued esophageal bleeding

• Stent dysfunction due to stenosis, thrombosis, retraction, kinking, or displacement - As many as 50% of shunts may occlude in 1 year

• Hemobilia

• Persistent gastric varices associated with spontaneous splenorenal collaterals or with massive splenomegaly

Complications

TIPS complications related to technique include the following:

• Neck hematoma

• Cardiac arrhythmia

• Perihepatic hematoma

• Rupture of liver capsule

• Extrahepatic puncture of portal vein

• Arterioportal fistula

• Portobiliary fistula

TIPS complications related to portosystemic shunting include: (1) hepatic encephalopathy (approximately 30%), (2) increased susceptibility to bacteremia, and (3) liver failure. Other complications may include TIPS-associated hemolysis (approximately 10%), stent infection, hemorrhage, and acute kidney injury associated with intraprocedural intravenous contrast administration. ^[56]

In patients with small varices (< 5 mm or minimally elevated veins above the esophageal mucosal surface), surveillance is preferred over other therapeutic modalities. In patients with medium to large varices (>5 mm or esophageal vein raised beyond mucosal surface occupying esophageal lumen) without a high risk of bleeding, a nonselective beta-blocker is the preferred first line treatment, although esophageal varices ligation (EVL) may be considered. ^{[8, 12]}

Patients at high risk for bleeding have large varices, red wale markings on the varices, and severe liver failure; either nonselective beta-blockers or EVL can be used as the primary prophylaxis. ^{[3, 8, 12, 57, 58, 59, 60]}

In patients with medium or large varices with bleeding stigmata regardless of the size, and patients with decompensated cirrhosis, nonselective beta-blockers are preferred as they have been shown to decrease the number of bleeding episodes. If contraindications, patient intolerance, or patient noncompliance exist regarding the use of nonselective beta-blockers, EVL should be considered. ^{[8, 12]}

If patients are on selective beta-blocker (eg, atenolol, metoprolol) for other indications, switching to a nonselective beta-blocker (eg, propanolol, nadolol, carvedilol) is necessary. Selective beta-blockers have been shown to be less effective than nonselective beta-blockers for the primary prophylaxis of variceal hemorrhage. ^[8]

Surveillance

All patients with liver cirrhosis should undergo a screening upper gastrointestinal (GI) endoscopy to determine their risk for bleeding. Patients without varices should have a follow-up upper GI endoscopy (surveillance esophagogastroduodenoscopy [EGD]) after 2 years, or sooner if they have signs of clinical decompensation (see Upper Gastrointestinal Endoscopy). Nonselective beta-blockers may be considered in those with decompensated cirrhosis (particularly when compliance with EGD surveillance is a concern), but these agents are not recommended in patients with compensated cirrhosis.

Patients with small varices should have repeat endoscopy annually ^{[8, 61]} ; surveillance EGD is preferred over beta-blockers as they do not prevent the development of varices and are associated with a higher incidence of adverse effects. ^[8] However, because EGD requires sedation and is expensive, it is not mandatory in patients who are already on nonselective beta-blockers for other reasons. ^[12]

Beta-blockers

Noncardioselective beta-blockers are used most commonly for primary prophylaxis of variceal bleeding, and they include propranolol and nadolol. These nonselective beta-blockers reduce portal and collateral blood flow as well as have smaller effects on the increase in portal resistance and decrease on portal pressure. Reduction in cardiac output (via blockade of beta1 adrenoreceptors) occurs, as does splanchnic vasoconstriction (via blockade of vasodilatory adrenoreceptors of the splanchnic circulation). ^{[3, 57, 58, 59, 60]}

Nonselective beta-blockers have been shown to decrease the risk of initial bleeding by approximately 45-50%, ^[12] and they reduce bleeding in more than 50% of patients with medium or large varices. ^[8] A meta-analysis of 11 trials evaluating nonselective beta-blockers in the prevention of first variceal bleeding showed that the bleeding rate in controls (25%) was significantly reduced (to 15%) in patients treated with beta-blockers after a median follow-up of 24 months. ^[58] The mortality rate also was lower in the beta-blocker group; however, the difference did not achieve statistical significance.

In the same meta-analysis, evaluation of the effects of beta-blockers as a function of variceal size showed the risk of first variceal bleeding in patients with medium to large varices was 30% in controls and 14% in patients treated with beta-blockers. ^[58] In patients with small varices, a tendency existed for reduction in the first bleeding episode; however, the number of patients and the rate of first bleeding were too low to achieve statistical significance. ^[58]

Propranolol is administered at a dose of 20 mg every 12 hours, which is increased or decreased every 3-4 days until a 25% reduction in the resting heart rate occurs or the heart rate is down to 55 beats per minute (bpm). The average dose of propranolol is usually 40 mg twice daily. Administering more than 320 mg/day is not recommended. Nadolol dosing is half the daily dose of propranolol, administered once daily.

Reduction in the heart rate may not lead to a reduction in the hepatic venous pressure gradient (HVPG); therefore, it is recommended that the dose should be titrated to the maximal tolerable dose until any adverse effects develop. Response to treatment is monitored by a reduction of the portal pressure gradient by more than 20% of the baseline value or less than 12 mm Hg. ^[12] However, checking the HVPG response in primary prophylaxis is not mandatory, because 60% of patients who do not achieve these targets still do not bleed at 2-year follow-up evaluations.

Propranolol is contraindicated in patients with asthma, chronic obstructive pulmonary disease (COPD), atrioventricular (AV) block, intermittent claudication, and psychosis. The most frequent adverse effects are lightheadedness, fatigue, dyspnea upon exertion, bronchospasm, insomnia, impotence, and apathy. ^[8] Reducing the dose of propranolol frequently controls these adverse effects.

A meta-analysis from China showed that carvedilol may be more effective in decreasing HVPG than propranolol or nebivolol. ^{[62, 63, 64]} ​ It may even be as effective as EVL or nadolol plus isosorbide mononitrate (ISMN) in preventing variceal bleeding. However large-scale randomized studies are required before firm conclusions can be made.

Beta-blockers are best continued for the patient's lifetime, because the risk of variceal hemorrhage returns to that of the untreated population once beta-blockers are withdrawn.

Vasodilators

The vasodilator ISMN may be considered as a second-line agent for secondary prophylaxis for variceal bleeding. The available evidence does not support the use of this agent as monotherapy for primary prophylaxis, even in patients with contraindications or intolerance to beta-blockers. One study reported ISMN to be as effective as propranolol in preventing first variceal bleeding, but long-term follow-up showed a higher mortality rate in patients older than 50 years in the ISMN group.

Vasodilators also reduce esophageal variceal pressure. The primary concern in patients with advanced cirrhosis is that vasodilators can reduce arterial blood pressure and promote the activation of endogenous vasoactive systems that may lead to sodium and water retention. Although ISMN has been demonstrated to reduce HVPG markedly in acute administration, it provides significantly less reduction after long-term administration (due to probable development of patient tolerance).

Combination therapy

Although many authorities recommended a combination therapy of pharmacologic treatment and EVL as the first-line treatment for secondary prophylaxis, ^{[8, 12, 20]} emerging evidences suggests that EVL alone is as effective as the combination therapy. ^[41]

Theoretically, combination therapy with beta-blockers and ISMN should offer better reduction in portal pressure, but this has not shown statistical significance in preventing rebleeding episodes in the clinical setting. A large, double-blind, placebo-controlled trial was unable to demonstrate a significantly lower rate of first hemorrhage in the group treated with combination therapy versus those given beta-blockers alone. ^[65] In addition, combination therapy appears to be associated with increased adverse effects and a higher rate of ascites. ^{[8, 12]}

Combination therapy cannot be recommended presently until further studies prove its efficacy. However, addition of ISMN should be considered when single pharmacotherapy fails.

Sclerotherapy

Sclerotherapy has no role in primary prophylaxis. Randomized, controlled trials investigating the use of sclerotherapy for primary prophylaxis produced divergent results, with some studies showing a worse outcome in patients who underwent this therapy than in controls. Moreover, combination treatment with sclerotherapy and nonselective beta-blockers offer no advantages over the use of beta-blockers alone for the prevention of esophageal variceal hemorrhage.

Endoscopic variceal ligation

Prophylactic EVL currently cannot be recommended as a routine measure for primary prevention as it offers no advantage over the use of beta-blockers alone for preventing esophageal variceal bleeding. ^[12] However, this procedure may be an option in secondary prophylaxis for patients with grade 3 varices who have contraindications to or cannot tolerate beta-blockers. ^{[8, 66]}

EVL has been demonstrated to be more effective than the administration of no treatment in preventing a first variceal bleed. It has also been shown to have an efficacy similar to that of beta-blockers in the prevention of first variceal bleeds, ^[67] but with increased adverse effects. (However, a study by Lay et al suggested that EVL is as safe as propranolol therapy in primary prophylaxis. The study involved 100 patients with cirrhosis—of whom half were treated with EVL and half received propranolol—who were at high risk of variceal bleeding. ^[68] )