Acute variceal bleeding is a potentially life-threatening complication of portal hypertension. Management consists of emergent hemostasis, therapy directed at hemodynamic resuscitation, protection of the airway, and prevention and treatment of complications including prophylactic use of antibiotics. Endoscopic treatment remains the mainstay in the management of acute variceal bleeding in combination with pharmacotherapy aimed at reducing portal pressure. This article intends to highlight only the current nonendoscopic treatment approaches for control of acute variceal bleeding.
Key points
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Initial stabilization and resuscitation is imperative in the management of acute variceal bleeding along with attention at prevention of associated complications such as hepatic encephalopathy, acute renal injury, spontaneous bacterial peritonitis, and sepsis.
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Urgent attention at achieving hemostasis through endoscopic means remains the key and should be supported by pharmacotherapy aiming at reducing portal venous pressure.
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Patients failing initial treatment should be rescued with transjugular intrahepatic portosystemic shunt, balloon-occluded retrograde transvenous obliteration, or rarely surgical shunts.
Acute variceal bleeding is a potentially life-threatening complication of portal hypertension defined as elevation of hepatic venous pressure gradient (HVPG) to greater than 5 mm Hg. Portal hypertension is classified as prehepatic, intrahepatic, or post-hepatic, intrahepatic being the form most often caused by cirrhosis, irrespective of the cause. Portal hypertension results in redistribution and increased blood flow through the coronary veins and the short gastric veins, resulting in esophageal and gastric varices. Gastroesophageal varices begin to form at a pressure gradient of 8 to 10 mm Hg, with bleeding risk increased at a gradient of 12 mm Hg. In patients without varices, esophageal varices develop and grow in size at a rate of about 7% per year as a result of ongoing portal hypertension. Variceal rupture could potentially occur in about one-third of patients, with the highest rates observed in patients with HVPG greater than 20 mm Hg and/or Child C patients with large varices with red wale markings. Acute variceal bleeding occurs in 25% to 40% of cirrhotic patients and carries a mortality of 25% to 30%, making it one of the most dreaded complications of portal hypertension. Bleeding usually occurs at the gastroesophageal junction because varices are most superficial and have the thinnest wall at this anatomic location. Approximately 50% of the acute variceal bleeding ceases spontaneously. After an index bleeding episode, most of the episodes of rebleeding occurs in the first 6 weeks and more than 50% of such rebleeding episodes occur within 3 to 4 days from the time of the initial bleeding episode. The risk factors for early rebleeding are severe initial bleeding as defined by a hemoglobin less than 8 g/dL, gastric variceal bleeding, thrombocytopenia, encephalopathy, alcohol-related cirrhosis, large varices, active bleeding during endoscopy, and a high HVPG. In the long term, approximately 70% of subjects experience further variceal bleeding and have a similar risk of mortality within the first year. Age greater than 60 years, large esophageal varices, severity of liver disease, continued alcoholism, renal failure, and presence of a hepatoma increase the risk of rebleeding.
Before the advent of pharmacotherapy, endoscopic therapy, and shunt procedures for control of variceal bleeding, almost 40% of patients with acute variceal hemorrhage died within 6 weeks, one-third rebled at 6 weeks, and only about one-third survived beyond 1 year.
Significant advances have been observed in the last 2 decades in the management of acute variceal bleeding by both endoscopic and nonendoscopic means and have resulted in significant reductions in both morbidity and mortality from this potentially life-threatening condition. Endoscopic treatment is important and remains the cornerstone in the management of acute variceal bleeding, and newer techniques are continuing to evolve. The current article, however, intends to highlight only the current nonendoscopic treatment approaches for control of acute variceal bleeding and recent developments.
Management of acute variceal bleeding
General Management
Acute variceal bleeding is a potentially life-threatening event. Most patients vomit blood but hematochezia and melena might be the only initial symptoms. Hemodynamic stability depends on the amount of blood lost; presentation could include symptoms of orthostatic hypotension to hemorrhagic shock. Despite advances in therapy, up to 40% of patients still die from exsanguinating bleeding. Of note, most deaths are unrelated to bleeding per se and are rather caused by complications of bleeding such as liver failure, infections, and hepatorenal syndrome. The degree of liver dysfunction, creatinine level, hypovolemic shock, active bleeding on endoscopy, and presence of hepatocellular carcinoma are important determinants of adverse outcome. Thus, the management of patients with acute variceal bleeding includes not only treatment and control of active bleeding but also the prevention of rebleeding, hepatic encephalopathy, infections, and renal failure. Available therapeutic options to control bleeding include medical and endoscopic treatment, balloon tamponade, placement of fully covered self-expandable metallic stents, transjugular intrahepatic portosystemic shunt (TIPS), and surgical shunts. Nowadays, the initial approach is a combination of vasoactive drugs, antibiotics, and endoscopic therapy, followed by a more aggressive approach in patients failing first-line treatment.
Management of acute variceal bleeding
General Management
Acute variceal bleeding is a potentially life-threatening event. Most patients vomit blood but hematochezia and melena might be the only initial symptoms. Hemodynamic stability depends on the amount of blood lost; presentation could include symptoms of orthostatic hypotension to hemorrhagic shock. Despite advances in therapy, up to 40% of patients still die from exsanguinating bleeding. Of note, most deaths are unrelated to bleeding per se and are rather caused by complications of bleeding such as liver failure, infections, and hepatorenal syndrome. The degree of liver dysfunction, creatinine level, hypovolemic shock, active bleeding on endoscopy, and presence of hepatocellular carcinoma are important determinants of adverse outcome. Thus, the management of patients with acute variceal bleeding includes not only treatment and control of active bleeding but also the prevention of rebleeding, hepatic encephalopathy, infections, and renal failure. Available therapeutic options to control bleeding include medical and endoscopic treatment, balloon tamponade, placement of fully covered self-expandable metallic stents, transjugular intrahepatic portosystemic shunt (TIPS), and surgical shunts. Nowadays, the initial approach is a combination of vasoactive drugs, antibiotics, and endoscopic therapy, followed by a more aggressive approach in patients failing first-line treatment.
Assessment of severity of bleeding
Assessment of the severity of variceal bleeding is of paramount importance to risk stratify the level of resuscitation. The Baveno II Consensus Conference defined an episode of acute variceal bleeding as clinically significant when there is blood transfusion requirement of at least 2 units and a systolic pressure less than 100 mm Hg, or a postural drop of 20 mm Hg and/or pulse rate greater than 100 beats per minute at time of patient presentation (ie, time zero). Management of acute variceal hemorrhage includes hemodynamic resuscitation, prevention and treatment of complications, and control of bleeding.
Resuscitation
Correction of hypovolemia
The foremost step is the assessment of intravascular volume loss and replacement with crystalloids and packed red blood cells to keep systolic blood pressure at least at 90 to 100 mm Hg and the heart rate less than 100 beats/min, with a hemoglobin level around 7 to 8 g/dL (hematocrit of 21–24). Care must be taken to avoid overtransfusion because this can cause a rebound increase in portal pressure and precipitate early rebleeding. Fresh frozen plasma and platelets (particularly for a platelet count <50,000/mL) have often been used to correct coagulopathy. These measures do not adequately correct the coagulopathy and could potentially induce volume overload and rebound portal hypertension. The use of recombinant factor VII has been shown to improve hemostasis rates, but it does not improve survival.
Aspiration precaution
Patients with acute variceal hemorrhage are at very high risk for aspiration pneumonia, which often progresses to multiorgan failure and has been associated with a very high mortality. It is therefore imperative to pay attention to the airway and protect the airway by prophylactic intubation when mental status is impaired, delirium tremens is imminent, or bleeding is too severe for the patient to maintain the integrity of their airway.
Prevention and Treatment of Associated Complications
Antibiotic prophylaxis
Bacterial infection is documented in 30% to 40% of cirrhotic patients on admission or within the first week after variceal bleeding, associated with an increased in-hospital mortality. The most common infections in these patients are spontaneous bacterial peritonitis and bacteremia, followed by urinary tract infections and pneumonia. Most infections are due to enterobacteria. Antibiotic prophylaxis significantly increases both the proportion of patients free from infection and the mean survival rate at 14 days.
Currently, it is recommended that short-term antibiotic prophylaxis, a measure that reduces bacterial infections, variceal rebleeding, and death, be used in every patient with cirrhosis admitted with gastrointestinal hemorrhage. The choice of antibiotics, however, is not standardized as different antibiotics have been used in different trials, and given different local antibiotic susceptibility patterns and different availability, it is unlikely that a definitive trial in this area will be performed. Quinolones in uncomplicated patients and ceftriaxone in high-risk patients with advanced liver disease (ascites, encephalopathy, jaundice, and malnutrition) or previous therapy with quinolones is a reasonable choice.
Hepatic encephalopathy
Hepatic encephalopathy is frequently precipitated after acute variceal hemorrhage. Digested blood in the gastrointestinal tract provides a source of extra protein, which is a source of excess ammonia and other toxic amines. Because of portosystemic shunting, the normal first-pass extraction by the liver is decreased and the circulating levels of these toxins increase, thereby contributing to the development of hepatic encephalopathy. Hepatic encephalopathy is also worsened by sepsis, azotemia, and electrolyte disturbances that can occur in the context of a variceal bleed. Of note, sedation used during endoscopy or for airway intubation may also contribute to altered mental status in such patients. Management of hepatic encephalopathy in the setting of acute variceal bleeding includes aggressive therapy with lactulose, either orally or by means of a nasogastric tube, in patient with altered mental status once bleeding is controlled and the gut is known to be functional. Although the role of rifaximin and other antibiotics for the treatment of encephalopathy in the setting of acute variceal bleeding is unclear, recent studies have shown a combination therapy of lactulose with rifaximin may be more useful than lactulose alone. For patients with persistent hepatic encephalopathy, especially those with Grade IV hepatic encephalopathy without improvement despite withdrawal of sedation and aggressive use of lactulose, an imaging study of the head (computed tomography scan or magnetic resonance imaging) and electroencephalogram should be considered.
Acute renal failure
Acute renal failure in a patient with cirrhosis is a severe complication and often a harbinger of death, whereas serum creatinine is a key component of the model for end-stage liver disease score, a well-established predictor of mortality. Renal failure in a patient with acute variceal bleeding is also a predictor of increased mortality, hence physicians should not just focus on the bleeding alone, but measures should be taken to prevent the occurrence of renal failure. The risk of renal failure can be minimized by careful attention to volume status, avoidance and aggressive treatment of sepsis, and avoidance of nephrotoxic drugs. An indwelling catheter should be used to monitor urine output, and the fluids administered should be tailored to maintain an output of at least 50 cc/h.
Achievement of Hemostasis
In the context of active bleeding, it is imperative to begin therapy quickly and control bleeding. Several modalities are available as first-line treatment of the achievement of hemostasis. These include pharmacologic treatment, endoscopic sclerotherapy, and variceal ligation. Several other modalities of treatment are available in patients failing standard measures as a rescue therapy such as balloon tamponade, placement of esophageal covered metal stent, TIPS, balloon-occluded retrograde transvenous obliteration (BRTO), and so on; a detailed discussion of these is beyond the scope of this article. Nonendoscopic measures to achieve hemostasis are discussed later in this article.
Balloon tamponade
Balloon tamponade is aimed at obtaining temporary hemostasis by direct compression of bleeding varices. The use of balloon tamponade for the treatment of acute esophageal variceal bleeding was introduced by Sengstaken and Blakemore. The Minnesota tube is a modified version with an aspiration channel above the esophageal balloon. For uncontrolled bleeding from gastric varices, the Linton-Nicholas tube is preferred. Balloon tamponade is highly successful in stopping bleeding in experienced hands, but recurrence is observed in about 50% of the patients within 24 hours following deflation of the balloon. Major complications, the most lethal of which is esophageal rupture, have been observed in 6% to 20% of patients, occurring more frequently in series in which tubes were inserted by inexperienced staff. It should be noted that balloon tamponade is only a bridging procedure for a more definitive procedure later on.
Pharmacotherapy
Based on the principle of hydromechanics, portal pressure is determined by intravascular resistance and blood flow. In portal hypertension, the intrahepatic vascular resistance (IHVR) and splanchnic blood flow are the 2 main contributors to portal pressure. IHVR is under dynamic regulation; postprandial increases in splanchnic blood flow is always associated with an autonomic down-regulation, leading to no alteration in portal pressure. However, in patients with cirrhosis, this delicate balance is lost, and the IHVR is significantly upregulated by mechanical and hemodynamic factors, which is further aggravated by splanchnic vasodilation. The resultant increase in portal pressure is the antecedent to variceal bleeding with its associated morbidity and high mortality. Most drugs currently used to treat varices and/or variceal hemorrhage cause splanchnic vasoconstriction, leading to a reduction in portal venous inflow and consequently to a decrease in portal pressure.
Vasopressin
Vasopressin (antidiuretic hormone) is a powerful vasoconstrictor that acts at the level of V1 receptors located in the smooth muscle of the arteries inducing contraction by activating phospholipase C and increasing cytosolic calcium [Ca ++ ] level through the inositol triphosphate pathway. The ability of vasopressin to control variceal bleeding is caused by powerful splanchnic arteriolar vasoconstriction, which decreases the portal inflow and thus the portal pressure. Unfortunately, vasopressin also causes profound systemic vasoconstriction with increased peripheral resistance and reduced cardiac output, heart rate, and coronary blood flow, leading to myocardial ischemia and/or infarction, cardiac arrhythmias, mesenteric ischemia, extremity ischemia, and cerebrovascular accidents in a sizable proportion of patients. In clinical trials, 32% to 64% of the patients treated with vasopressin experienced adverse effects and almost 25% had to be taken off the drug. Fatal complications caused by vasopressin also have been reported. The systemic vasoconstrictive adverse effects of vasopressin may be minimized by the concomitant use of nitrates. Vasopressin is administered as a continuous infusion at a rate of 0.2 to 0.4 U/min that may be increased to 0.6 U/min if required. Therapy is maintained for 24 hours after the control of bleeding. Vasopressin rarely is used today in the management of variceal bleeding because of its adverse effect profile.
Terlipressin (Glypressin)
Triglycyl-lysl-vasopressin (terlipressin), a synthetic analogue of vasopressin, is in itself inactive but is activated after the glycyl residue is cleaved releasing vasopressin slowly and continuously causing splanchnic vasoconstriction. Terlipressin has a longer biological half-life and is administered every 4 hours, and thus continuous infusion is not needed. Terlipressin does not increase the plasminogen activator activity, as is seen with vasopressin, but has similar effects on the coronary vasculature.
Somatostatin and analogues
Somatostatin is a naturally occurring peptide originally named for its growth hormone–inhibiting properties. Somatostatin causes an increase in splanchnic vascular resistance by causing vasoconstriction resulting in decrease in the portal blood inflow. The vasoconstriction is mediated by inhibiting the release of splanchnic vasodilator hormones like glucagon and vasoactive intestinal peptide. In addition, somatostatin also acts by preventing post-prandial hyperemia and also causes a modest decrease in the hepatic blood flow and the wedged hepatic venous pressure (WHVP). Somatostatin has a short half-life and is rapidly cleared from the blood. Somatostatin is given as an intravenous bolus of 250 μg, followed by a continuous infusion of 250 μg/h; the therapy is continued for 2 to 5 days if successful. A bolus of somatostatin markedly decreases the HVPG by 52% at 1 minute, 19% at 3 minutes, and 13% at 5 minutes.
In current clinical practice and clinical trials, the synthetic analogues of somatostatin, namely octreotide and vapreotide, have been most widely used in the management of acute variceal bleeding and have a longer duration of action. Octreotide produces a modest decline in the WHVP and a variable effect on intravariceal pressure. Additionally, it significantly decreases azygos blood flow and has an excellent safety profile in the absence of the systemic circulatory adverse effects as seen with vasopressin. Octreotide is a synthetic analogue of somatostatin with longer half-life. It is administered as an initial bolus of 50 μg, followed by an infusion of 50 μg/h. The complication rates with somatostatin and octreotide are few but can include mild hyperglycemia and abdominal cramping.
Radiological intervention
Transjugular intrahepatic portosystemic shunt for acute variceal bleeding
TIPS is an artificial channel within the liver that establishes communication between the inflow portal vein and the outflow hepatic vein. The procedure is usually performed by an interventional radiologist, who creates the shunt using a fluoroscopy-guided endovascular approach, with the jugular vein as the usual entry site, from which a catheter is advanced to gain access to the patient’s hepatic vein by traveling from the superior vena cava into the inferior vena cava and finally the hepatic vein. Once the catheter is in the hepatic vein, a branch of the portal vein within the liver is then catheterized with placement of an expandable stent from the hepatic vein into the branch of the portal vein. The success rate with TIPS for decompression of the portal vein is high—more than 90% of cases in most case series. Guidelines have been established by the Society of Interventional Radiology for creation of a TIPS, and the consensus was that a technically successful outcome is creation of the shunt with a decrease in portal pressure to less than 12 mm Hg that should be achieved in 95% of patients, and resolution of the complication of portal hypertension should be achieved in 90% of cases.
In general, pharmacologic therapy and endoscopic banding achieve control of variceal bleeding in most of the cases; failures to standard therapy occur in about 10% to 20% of patients, and in these subgroups TIPS could potentially be lifesaving. As discussed earlier, the success rate of TIPS to achieve decompression of the portal vein is more than 90%, nevertheless, mortality at 6 weeks among patients treated with rescue TIPS for uncontrolled index bleeding and rebleeding is very high (35%), reflecting the severity of their underlying liver disease as well as additional organ dysfunction that may have occurred owing to hypotension, infection, and aspiration.
It is thus important to identify patients at high risk of failing standard therapy, because these patients could potentially be offered TIPS early on. The most important predictor of failure to standard therapy is HVPG greater than 20 mm Hg measured within 24 hours of admission. Unfortunately, such measurements are not feasible in most centers, and Child’s status is used as a surrogate marker, because Child’s C status correlates with the likelihood of having an HVPG above 20 mm Hg in more than 85% of patients. To verify the utility of preemptive TIPS, 2 trials in patients with acute variceal hemorrhage at high risk of failing standard therapy were conducted. In the first, a single-center trial, 52 patients with an HVPG greater than 20 mm Hg were randomized to (uncoated) TIPS within 24 hours of admission versus continuing standard therapy. In the second trial, a multicenter European study, 63 Child class C patients (excluding those with the highest scores of 14 and 15) or Child class B patients with active bleeding were randomized to (polytetrafluoroethylene-coated) TIPS within 24 to 72 hours of admission versus continued standard therapy. Both trials showed a significant advantage of TIPS with a reduction in composite outcomes (failure to control bleeding or early rebleeding) and, importantly, a significantly higher survival. Usefulness of early TIPS in acute variceal hemorrhage and high risk of treatment failure has been further confirmed in a recent retrospective trial with a lower incidence of failure to control bleeding or rebleeding as well as reduced mortality. These studies recommended that early (preemptive) TIPS (<72 hours) should be considered for patients with variceal bleeding who are Child class C (14 points) or are Child class B with active bleeding ( Fig. 1 ). A recent economic modeling study has further confirmed early TIPS insertion is to be a cost-effective intervention in selected high-risk patients. Importantly, the subpopulation of patients with variceal bleeding who would be candidates for early TIPS represent less than 20% of the patients admitted with this complication. In the rest of the patients, the majority, TIPS is considered second-line therapy and is reserved for patients who fail standard therapy.
