Portal hypertensive bleeding: The role of portosystemic shunting

Prophylaxis

β-Blocker therapy has been studied to test its efficacy in preventing primary variceal hemorrhage in patients with known varices (see Chapter 80 ). Nadolol is an essential nonselective β-blocker, blocking both β ₁ and β ₂ receptors. Patients given nadolol were compared with untreated control individuals. Nadolol reduced the incidence of bleeding from 35% ± 3% to 12% ± 3%, and the incidence of fatal bleeds was reduced from 18% ± 3% to 10% ± 2%. There was no difference in the overall mortality rate. This study has been used to support the use of prophylactic β-blockade to prevent initial variceal hemorrhage. More recently, carvedilol, a nonselective β-blocker with additional α ₁ -blocking effect, appears to be better at reducing the hepatic venous wedge pressure gradient when compared with nonselective agents such as nadolol, and has gained interest as primary prophylaxis against variceal bleeding.

Nitrates are vasodilators whose action is mediated by nitric oxide on vascular smooth muscle. Nitroglycerin decreases portal pressure in patients with cirrhosis when high doses are used. In animal studies, nitroglycerin lowered portal pressure 13% and systemic blood pressure decreased 25%. This drug lowers portal pressure less than systemic pressure. Nitrates in combination with β-blockade may offer prophylaxis against an initial variceal bleed.

Clinical randomized controlled trials (RCTs) comparing nonselective β-blockers (propranolol or nadolol) with no therapy in cirrhotic patients showed that drug treatment effectively reduced the risk of a first variceal hemorrhage. The combination of isosorbide mononitrate and β-blockade further reduces portal pressure and has been shown in three studies to effectively reduce the risk of a first variceal bleed compared with β-blockade alone. These investigations have noted, however, the difficult problem of compliance, particularly in patients with alcoholism. In addition, fatigue may be a side effect of therapy with β-blockade, and even more seriously, if patients do bleed, their ability to compensate for blood loss by tachycardia is compromised.

Acute variceal hemorrhage (see Chapter 81 )

The posterior pituitary hormone vasopressin causes splanchnic arteriolar vasoconstriction, reducing portal blood pressure by approximately 15% when given intraarterially or intravenously. ^, Intravenous use is preferred for safety and convenience, and the optimal dose of the drug is 0.3 to 0.4 U/min intravenously. As a result of simultaneous vasoconstrictive effects on the cardiac, mesenteric, and cerebral circulations, the complications increase when doses of 0.5 to 0.7 U/min are administered. It is not necessary to taper the dose; the infusion can be stopped when the therapeutic end point is reached. In a controlled study comparing vasopressin with no therapy, approximately half of the patients on vasopressin stopped bleeding, but this result did not differ from control subjects. ^,

Nitroglycerin is often administered concurrently with vasopressin to reduce the systemic vasoconstrictive effects of vasopressin, and it may further reduce portal pressure. Nitroglycerin infusion begins at 40 μg/min and is titrated to a mean arterial blood pressure of 65 to 75 mm Hg.

Octreotide reduces bleeding and enhances the results of sclerotherapy. Somatostatin and octreotide are endogenous peptides that act by reducing splanchnic, hepatic, and azygos blood flow. Their principal advantage versus vasopressin is that they do not cause vasoconstriction of the myocardial and cerebral circulations. Somatostatin and octreotide should be administered continuously at 250 μg/hr and increased to 500 μg/hr if bleeding continues. Preliminary studies demonstrated that octreotide helped arrest acute variceal bleeding in six of six patients. ^, RCTs comparing somatostatin or octreotide with vasopressin versus no infusion have shown equivocal results, which suggests that vasopressin and somatostatin have similar efficacy. Neither vasopressin, somatostatin, nor terlipressin has been approved by the US Food and Drug Administration for treatment of variceal bleeding, although these agents are commonly used for this purpose. A prospective RCT showed equivalence of terlipressin, somatostatin, or octreotide, followed by endoscopic treatment of acute variceal bleeding.

Prevention of rebleeding after initial control

Propranolol was shown by Lebrec and colleagues ^, to reduce rebleeding significantly after acute variceal hemorrhage (see Chapter 80 ). This effect may be mediated by a decrease in cardiac output (β ₁ -blockade), increased splanchnic arteriolar resistance (β ₂ -blockade), and consequent decrease in portal blood flow and collateral blood flow via the azygos venous system. β-Blockade is not widely used in the United States to prevent rebleeding after an episode of variceal hemorrhage because endoscopic ligation is preferred, and β-blockade after acute bleeding has not been shown to reduce mortality. Meta-analysis comparing β-blockade with endoscopic therapy demonstrated a nonstatistically significant decrease in pooled relative risk for bleeding in the sclerotherapy group and no difference in mortality between the two groups. An RCT showed, however, that isosorbide mononitrate (80 mg/day) in combination with nadolol (80 mg/day) was more effective than sclerotherapy in reducing rebleeding, and complications were less frequent in the group treated with drugs (16% vs. 37%). A Taiwan study reported that following endoscopic variceal ligation (EVL) to control acute variceal bleeding, proton pump inhibitor infusion was similar to combination with vasoconstrictor infusion in terms of initial hemostasis, very early rebleeding rate, and associated with fewer adverse events. In summary, multimodal pharmacologic therapy plays a principal role in the United States in the prevention of rebleeding.

Prophylaxis

The use of prophylactic sclerotherapy to prevent a first hemorrhage was studied in three meta-analyses ^{, ,} (see Chapters 80 and 81 ). One study concluded that paravariceal injection with polidocanol decreased mortality rates. The other two reports found that prophylactic sclerotherapy did not reduce bleeding or mortality rate and concluded that sclerotherapy was not indicated in this setting. ^{, ,} The largest trial of prophylactic sclerotherapy was the Veterans Affairs (VA) cooperative trial. This trial included 281 patients but was prematurely closed because of excess mortality rate in the sclerotherapy group. Sclerotherapy prevented variceal hemorrhage but substituted bleeding from sclerotherapy-induced ulceration. This study effectively ended the use of prophylactic sclerotherapy in the United States.

Acute variceal hemorrhage

When it became apparent that the once predominant therapy for variceal hemorrhage (emergency surgical shunts) was not improving survival but substituting death from liver failure for death from bleeding, endoscopic variceal injection was evaluated as a less invasive therapy (see Chapter 81 ). In 1980 a prospective randomized trial with 107 patients from King’s College Hospital showed control of bleeding by sclerotherapy in 57% of 51 treated patients compared with 25% of 56 patients treated medically. Two years later, a follow-up study showed improved patient survival with sclerotherapy compared with controls who received blood transfusions, vasopressin, and a Sengstaken-Blakemore tube when necessary.

When interpreting this and subsequent trials, it is important to understand that the King’s College trial had more nonalcoholic patients than alcoholic patients (60 vs. 47) and had patients with relatively mild liver failure (74 were CTP class A or B; 33 were class C). The more patients in any study of variceal hemorrhage who are alcoholic or who have CTP class C liver disease, the more difficult it is to show a survival advantage of therapy. Death from bleeding in such patients tends to be replaced by death from liver failure (see Chapter 77 ). The VA cooperative study showed no reduction of long-term survival when acute hemorrhage was treated with sclerotherapy.

EVL was developed as an endoscopic alternative to sclerotherapy, potentially lowering the risk of ulceration and perforation of the esophagus.(see Chapters 80 and 81 ). Seven prospective RCTs compared EVL with endoscopic sclerotherapy. In all studies, EVL and sclerotherapy were equally effective in controlling active bleeding. Complications were significantly lower with EVL in all studies. No esophageal strictures were seen in patients treated with EVL compared with 5% to 33% of patients treated with sclerotherapy. The development of the multiband ligating device, which allows banding without repeated reinsertions of the endoscope, made this modality of endoscopic control of varices much more attractive such that it has become the endoscopic therapy of choice.

Prevention of rebleeding

Although EVL effectively stops acute variceal bleeding, rebleeding remains a problem, and intermediate (2- to 5-year) survival is not improved in many trials. A confounding variable confusing interpretation of the results in many of these trials is continued alcoholism. Alcohol abstinence for 6 months, CTP class, and aspartate aminotransferase level all were independent predictors of survival in the VA trial. When EVL was compared with sclerotherapy, rebleeding rates were significantly decreased with EVL in three studies, ^{, ,} and mortality rates were significantly lower in three studies. ^, As a result, EVL has emerged as the principal therapy in preventing rebleeding (see Chapters 80 and 81 ).

Following an episode of variceal bleeding, prophylactic antibiotics decreases the risk of rebleeding and is superior to use of antibiotics in response to signs and symptoms of infection. Ceftriaxone 1 g intravenously every day for up to 7 days or norfloxacin 400 mg orally daily for up to 7 days is recommended.