Acute variceal hemorrhage (AVH) is a lethal complication of portal hypertension and should be suspected in every patient with liver cirrhosis who presents with upper gastrointestinal bleed. AVH-related mortality has decreased in the last few decades from 40% to 15%–20% due to advances in the general and specific management of variceal hemorrhage. This review summarizes current management of AVH and prevention of recurrent hemorrhage with a focus on pharmacologic therapy.
Key points
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Variceal hemorrhage is a complication of cirrhosis that is mostly due to portal hypertension.
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Pharmacologic therapy for portal hypertension consists of splanchnic vasoconstrictors that decrease portal venous inflow or intrahepatic vasodilators that decrease intrahepatic resistance.
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Pharmacologic therapy for acute variceal hemorrhage consists of intravenous vasoconstrictors and antibiotics.
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Pharmacologic therapy to prevent recurrent variceal hemorrhage is based mainly on the use of nonselective β-blockers with or without nitrates.
Introduction
Acute variceal hemorrhage (AVH) is a medical emergency, and one of the complications of portal hypertension that define the development of decompensated cirrhosis. Approximately half of the patients with cirrhosis have gastroesophageal varices and one-third of all patients with varices will develop AVH, a complication that still carries a mortality of up to 15% to 20% despite all recent medical advances. This review summarizes the current standard pharmacologic management of AVH in the context of cirrhosis-related portal hypertension. Discussed is not only treatment of the acute episode of variceal hemorrhage but also the prevention of recurrent variceal hemorrhage, which is an integral part of the management of any patient with AVH. The recommendations made are mostly based on evidence in literature that has been summarized and prioritized at consensus conferences.
Introduction
Acute variceal hemorrhage (AVH) is a medical emergency, and one of the complications of portal hypertension that define the development of decompensated cirrhosis. Approximately half of the patients with cirrhosis have gastroesophageal varices and one-third of all patients with varices will develop AVH, a complication that still carries a mortality of up to 15% to 20% despite all recent medical advances. This review summarizes the current standard pharmacologic management of AVH in the context of cirrhosis-related portal hypertension. Discussed is not only treatment of the acute episode of variceal hemorrhage but also the prevention of recurrent variceal hemorrhage, which is an integral part of the management of any patient with AVH. The recommendations made are mostly based on evidence in literature that has been summarized and prioritized at consensus conferences.
Pathophysiology of portal hypertension
An understanding of pathophysiology of portal hypertension is important to understand the basis for the pharmacologic management of variceal hemorrhage. An increase in intrahepatic resistance is the initial mechanism of portal hypertension. Intrahepatic resistance results mainly from progressive architectural distortion (a fixed component), but one-third is due to intrahepatic vasoconstriction secondary to endothelial dysfunction with a deficiency in nitric oxide (NO) being the predominant abnormality. As intrahepatic resistance increases, portal flow is diverted through portosystemic collaterals that develop through pre-existing vessels that would normally drain blood into the portal vein and probably also through vessels that are newly formed (neoangiogenesis through an increase in vascular endothelial growth factor). Despite diversion of blood through collaterals and some attenuation of portal pressure, increased portal venous inflow sustains and progressively worsens portal hypertension. Portal inflow results from splanchnic vasodilatation, and the main contributor is an increase in NO. Therefore, in cirrhosis, NO is low in the intrahepatic circulation (vasoconstricted) but elevated in the splanchnic circulation (vasodilated).
In patients with cirrhosis, mostly of an alcoholic or viral cause, indirect measurement of portal pressure by hepatic vein catheterization and determination of the hepatic venous pressure gradient (HVPG) has been shown to be the best predictor of different stages in the development of varices and variceal hemorrhage. Normal HVPG is 3 to 5 mm Hg. An HVPG between 5 and 9.5 mm Hg indicates the presence of a silent stage of portal hypertension. Once the HVPG reaches and surpasses a threshold of 10 mm Hg (the so-called clinically significant portal hypertension), patients are at a higher risk of developing varices and cirrhosis decompensation. Almost all patients with gastroesophageal varices have reached an HVPG threshold of at least 12 mm Hg. In patients who present with AVH, a threshold of greater than 20 mm Hg identifies those with a higher risk for treatment failure and death. Conversely, decreases in HVPG are predictive of favorable outcomes. A decrease greater than 10% from baseline identifies a subgroup of patients without varices that is less likely to develop varices over time and identifies a subgroup of patients with large varices that is less likely to develop variceal hemorrhage. Patients with a history of variceal hemorrhage, a decrease in HVPG to less than 12 mm Hg, or a decrease greater than 20% from baseline (the so-called HVPG responders), are at a significantly reduced risk of recurrent variceal hemorrhage and show improved survival.
Therefore, reduction in portal pressure is the main goal of therapy in patients with variceal hemorrhage. Targets of pharmacologic therapy consist of drugs that will reduce portal pressure by decreasing portal venous inflow or by decreasing intrahepatic resistance. In the following section, drugs used in the treatment of AVH and in the prevention of recurrent variceal hemorrhage are described.
Drugs used in the treatment of acute variceal hemorrhage by mechanism of action
Drugs That Act by Decreasing Portal Flow
Splanchnic vasoconstrictors decrease portal flow by constricting arterioles that feed the intestine and thereby reduce blood flow into the portal vein. Intravenous vasoconstrictors, such as vasopressin and analogues (terlipressin) and somatostatin analogues (octreotide, vapreotide), are used in the acute intrahospital therapy for AVH. Splanchnic vasoconstrictors used in long-term treatment of primary and secondary prophylaxis of variceal hemorrhage are nonselective β-adrenergic blockers (NSBB). Antibiotics are another category of drugs that possibly act by decreasing portal flow.
Vasopressin and analogues
Vasopressin is a potent vasoconstrictor of both systemic and splanchnic circulation. In a study, an intravenous vasopressin injection resulted in a reduction of HVPG of 23% and intravariceal pressure of 14%. Addition of nitroglycerin has been shown to reduce many side effects of vasopressin and has a synergistic effect in reducing portal pressure. However, vasopressin use has been abandoned in the therapy for AVH because of its numerous side effects, including arterial hypertension, myocardial and peripheral vascular ischemia, limb gangrene, hyponatremia, and fluid retention.
Terlipressin is a long-acting triglycyl lysine derivative of vasopressin. Clinical studies have shown that the frequency and severity of side effects are lower with terlipressin compared with vasopressin. The most common side effect is abdominal pain. The overall efficacy of terlipressin in controlling AVH is 75% to 80% at 48 hours and of 67% at 5 days. Terlipressin is currently not approved for use in the United States.
Somatostatin and analogues
Somatostatin and analogues (octreotide, vapreotide) cause splanchnic vasoconstriction by inhibiting the release of vasodilator glucagon and also by a local mesenteric vasoconstrictive effect. However, the primary mechanism for the control of AVH may be through blunting of postprandial splanchnic hyperemia.
Intravenous boluses of somatostatin and octreotide cause significant transient reductions in portal pressure. Continuous infusion of somatostatin has a mild but sustained effect in reduction of portal pressure, but octreotide does not result in a sustained reduction in portal pressure. This rapid desensitization to the effects of octerotide infusion may explain the divergent effects achieved with octreotide in acute variceal bleeding. These drugs have a short half-life and are used in a continuous intravenous infusion for AVH. Unlike other vasoactive drugs, somatostatin and analogues have fewer side effects. Octreotide is the only vasoactive drug available in the United States for control of acute variceal bleeding, although its use in this setting is off-label.
Antibiotics
Bacterial infections by inducing the production of vasodilating cytokines that cause vasodilatation can theoretically lead to an increase in portal pressure, and the development of infections has been shown to increase the rate of treatment failure in patients with AVH. Infections can also precipitate renal and liver failure through worsening of effective hypovolemia and impaired oxygen utilization. Antibiotics used in the setting of AVH have been shown to improve survival after AVH likely due to decreased infections and rebleeding.
Nonselective β-blockers
In the setting of AVH, these drugs are used in the prevention of recurrent variceal hemorrhage not in the management of AVH because they can cause hypotension in potentially hemodynamically unstable patients. NSBB decrease portal pressure by unopposed α-adrenergic-mediated splanchnic vasoconstriction (β-2 antagonist effect) and by reducing cardiac output (β-1 antagonist effect).
NSBB use is associated with a median reduction in HVPG of approximately 15%, with only 37% of the patients being hemodynamic responders (ie, achieving a reduction in HVPG to <12 mm Hg or a reduction >20% from baseline). The high percentage of HVPG nonresponders on NSBB, despite adequate β-blockade, may be due to a concomitant increase in portocollateral resistance.
In many randomized clinical trials (RCTs), the dose of NSBB was adjusted to obtain a 25% decrease in heart rate; however, because a change in heart rate is not predictive of a decrease in portal pressure, recent guidelines have recommended the adjustment of NSBB to the highest tolerated dose or to a heart rate of 50 to 55 beats per minute. Measuring the hemodynamic response to a β- blocker is the best way to determine a pharmacologic effect on portal hypertension, and this could actually be done by determining the acute HVPG response to intravenous propranolol. However, the HVPG technique is not adequately practiced or standardized in most sites and therefore cannot be widely recommended.
NSBB commonly used clinically are nadolol and propranolol. Nadolol is longer acting, can be given once a day, is not metabolized by the liver, crosses blood-brain barrier to a lesser extent, and is better tolerated. The disadvantage of NSBB is that approximately 15% of patients may have relative or absolute contraindications to therapy, and that another 15% require dose reduction or discontinuation because of its common side effects (including fatigue, shortness of breath, and hypotension).
Drugs That Act by Reducing Intrahepatic Resistance
Drugs that will act on the intrahepatic circulation by causing vasodilation can reduce portal pressure and can potentially lead to increased flow through the liver and an improved liver function.
Nitrates
In the setting of AVH, and as mentioned above, nitrates have been used in combination with vasopressin. The addition of nitrates not only decreases the rate of side effects of vasopressin related to vasoconstriction, but also has an additive effect in reducing portal pressure. Nitrates alone seem to decrease portal pressure by their systemic hypotensive effect with a resultant reduction in cardiac output rather than by intrahepatic vasodilation. Therefore, nitrates used alone have no role in the treatment of portal hypertension because this hypotensive effect is potentially deleterious.
Nitrates can also be used in combination with NSBB for the prevention of rebleeding after AVH. Isosorbide-5-mononitrate (ISMN) is the long-acting nitrate of choice in patients with cirrhosis because of minimal first-pass metabolism. Compared with HVPG reduction of 15% with NSBB alone, combining either ISMN or prazosin with NSBB results in HVPG reduction of around 20% to 24%. The rate of HVPG responders with NSBB plus ISMN is 44%, a rate that is significantly higher than that observed with NSBB alone (37%). However, this combination is associated with more side effects and most patients cannot tolerate it.
Simvastatin
Simvastatin decreases intrahepatic vascular resistance resulting in vasodilation of liver vasculature in cirrhotic liver; this occurs because of upregulation of NO production through an enhancement in endothelial NO synthase activity as shown recently in both animals and humans. In a placebo-controlled double-blind RCT of 59 patients, 1-month simvastatin administration was associated with a significant reduction in HVPG 8%, with 32% of hemodynamic responders. These effects were additive with those of β-blockers.
A recent RCT compared the addition of simvastatin versus placebo in patients receiving standard therapy (ligation and drugs) and, although it showed a lacking effect on recurrent variceal hemorrhage, it showed a beneficial effect on survival.
Drugs That Act by Reducing Both Flow and Resistance
As mentioned previously, nitrates have been used in combination with vasopressin (in the control of AVH) and in combination with NSBB for the prevention of variceal rebleeding.
Carvedilol is a drug that is NSBB with additional vasodilating effect due to a weak α-1 antagonist activity that has been mostly tested in the prevention of first variceal hemorrhage, where low doses have a greater portal pressure-reducing effect than β-blockers, particularly in Child class A patients. In a recent RCT, carvedilol was as effective as nadolol plus ISMN in the secondary prophylaxis with fewer severe side effects and similar survival.
However, as these patients are more decompensated, the vasodilatory effect of carvedilol may cause further hypotension and potentially lead to fluid retention and renal injury as has been shown to occur in proof-of-concept studies. Therefore, until more data are available, carvedilol should be used cautiously in this setting.
Pharmacologic therapy in the different clinical settings
Control of Acute Variceal Hemorrhage
AVH is associated with significant mortality, morbidity, and health care cost and should be suspected in every patient with cirrhosis presenting with upper gastrointestinal bleed.
Initial resuscitation
These patients generally require management in the intensive care setting. The initial resuscitation follows basic principles of ABC (airway, breathing, and circulation) to achieve hemodynamic stability. The goal is to correct or prevent hypovolemic shock (crystalloids, transfusion) and complications associated with gastrointestinal bleed (bacterial infections, renal failure, hepatic decompensation). Intubation is required if the risk of aspiration is high as in deeply encephalopathic patients. In patients who are hemodynamically stable, transfusion of packed red blood cells should be done conservatively at a target hemoglobin levels between 7 and 8 g/dL because a recent RCT in patients with acute upper gastrointestinal hemorrhage showed that a restrictive transfusion strategy (transfusion when hemoglobin decreases to <7 g/dL) is associated with a better survival than a liberal transfusion strategy (transfusion when hemoglobin decreases to <9 g/dL) to restrictive strategy (transfusion when the hemoglobin decreased to <7 g/dL). In a subset of patients with cirrhosis, the restrictive strategy was associated with significantly less rebleeding and improved survival, particularly in those belonging to Child class A and B. Portal pressure increased in those in the liberal transfusion group but not in those in the restrictive transfusion group.
The prothrombin time/international normalized ratio is not a reliable indicator of the coagulation status in patients with cirrhosis because of a concomitant decrease of both procoagulants and anticoagulants. Proof of this is a multicenter randomized, placebo-controlled trial of recombinant factor VIIa that showed no benefit regarding the ability to control 24-hour bleeding or to prevent rebleeding or death at day 5 in Child class B and C patients with AVH.
Prophylactic antibiotics
Bacterial infections occur in up to 35% to 66% of patients with AVH depending on the severity of liver disease. Infection is an independent prognostic indicator of rebleeding within 7 days. In a meta-analysis of 5 trials, prophylactic antibiotics were found to significantly decrease the risk of infections and rebleeding and improve the survival rate. Therefore, prophylactic antibiotics are currently recommended in all cirrhotic patients with AVH ( Table 1 ). The preferred antibiotic for most patients is an oral quinolone, although intravenous ceftriaxone is preferable in patients with advanced cirrhosis or high prevalence of quinolone resistance or in patients already on quinolone prophylaxis. However, given the increasing rate of infections due to multi-drug-resistant organisms and their close relationship with the widespread use of antibiotics, high-risk populations that will benefit from antibiotics should be identified. A recent retrospective study suggests that Child class A patients with AVH may not require prophylactic antibiotics because they are shown have a low risk of infection and death even in the absence of antibiotic prophylaxis.
Related posts:
Advances and Improvements in the Management of Upper Gastrointestinal Bleeding
Epidemiology and Risk Factors for Upper Gastrointestinal Bleeding
Endoscopic Diagnosis and Therapy in Gastroesophageal Variceal Bleeding
Injection and Cautery Methods for Nonvariceal Bleeding Control
Unusual Causes of Upper Gastrointestinal Bleeding
Tips and Tricks on How to Optimally Manage Patients with Upper Gastrointestinal Bleeding
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