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  • 1. PRESENTATION The Treatment of Acute Variceal Bleeding Juan G. Abraldes, MD*w and Jaime Bosch, MD*w first 5 days with 40% of all rebleeding episodes occurring Abstract: Bleeding from gastroesophageal varices is a frequent in this very early period, remain high during the first 2 and often deadly complication of cirrhosis. Although mortality weeks and decline then slowly in the next 4 weeks. After 6 from an episode of variceal bleeding has decreased in the last weeks the risk of further bleeding becomes virtually equal 2 decades it is still around 20%. This paper reviews the most to that before bleeding.4 Currently available treatments recent advancements in the general management and hemostatic have reduced 6-week rebleeding to 20%.1 Early rebleed- treatments of acute variceal bleeding. ing is a strong predictor of death from variceal bleeding. Key Word: portal hypertension Prognostic indicators for early rebleeding were assessed in most studies together with initial failure to control (J Clin Gastroenterol 2007;41:S312–S317) bleeding and 5-day risk for death, as a composite end point referred to as ‘‘5-day failure.’’ Bacterial infection,5,6 active bleeding at emergency endoscopy,1,6 Child-Pugh class or score,1,6,7 aspartate aminotransferase levels,1 NATURAL HISTORY AND PROGNOSIS presence of portal vein thrombosis,1 and a hepatic venous pressure gradient (HVPG) >20 mm Hg measured shortly Ruptured esophageal varices cause 70% of all upper after admission7–9 have been reported as significant gastrointestinal bleeding episodes in patients with portal predictors of risk for 5-day failure. hypertension.1 Thus, in any cirrhotic patient with acute upper gastrointestinal bleeding, a variceal origin should be suspected. Diagnosis is established at emergency Mortality endoscopy on the basis of observing one of the following: Mortality from variceal bleeding has greatly de- active bleeding from a varix (observation of blood creased in the last 2 decades, from 42% mortality in the spurting or oozing from the varix), white nipple or clot Graham and Smith4 study in 1981 to the current 15% adherent to a varix, and presence of varices without other to 20%.1,10–12 This is probably due to implementation potential sources of bleeding. of effective treatments [endoscopic and pharmacologic therapies and transjugular intrahepatic portosystemic Initial Control of Bleeding stent-shunt (TIPS)], and from improved general medical Because variceal bleeding is frequently intermittent, care (ie, antibiotic prophylaxis). Because it may be it is difficult to assess when the bleeding stops and when a difficult to assess the true cause of death (ie, bleeding new hematemesis or melena should be considered an vs. liver failure or other adverse events), the general episode of rebleeding. Several consensus conferences have consensus is that any death occurring within 6 weeks from addressed this issue and set definitions for events and hospital admission for variceal bleeding should be timing of events related to episodes of variceal bleeding.2 considered as a bleeding-related death.2 Immediate Using these definitions, data from placebo-controlled mortality from uncontrolled bleeding is in the range of clinical trials show that variceal bleeding is spontaneously 4% to 8%.1,13 Prehospital mortality from variceal controlled in 40% to 50% of patients.3 Currently bleeding might be around 3%.14 The risk for mortality available treatments increase control of bleeding to about peaks the first days after bleeding, slowly declines 80% of the patients.1 thereafter, and after 6 weeks becomes constant and virtually equal to that before bleeding.3,4 Nowadays only Early Rebleeding 40% of the deaths are directly related to bleeding, The incidence of early rebleeding ranges between whereas most are caused by liver failure, infections, and 30% and 40% in the first 6 weeks. The risk peaks in the hepatorenal syndrome.1 Thus, although there is still room for improving hemostatic treatments, to substantially decrease mortality from variceal bleeding therapies Received for publication July 3, 2007; accepted July 6, 2007. should be able to prevent deterioration of liver and renal From the *Hepatic Hemodynamic Laboratory, Liver Unit, Institut Malalties Digestives i Metaboliques, Hospital Clı´ nic; and wCiberehd ´ function. ` and Institut d’Investigacions Biomediques August Pi i Sunyer The most consistently reported death risk indicators (IDIBAPS), University of Barcelona, Barcelona, Spain. are Child-Pugh classification or its components, blood ´ Supported in part by Fondo de Investigacion Sanitaria (PI 050519 to urea nitrogen or creatinine, active bleeding on endoscopy, Juan G. Abraldes and 05/1285+06/0623 to Jaime Bosch). Reprints: Juan G. Abraldes, MD, Liver Unit, Hospital Clı´ nic, Villarroel hypovolemic shock, and hepatocellular carcinoma.1,4,5,15 170, Barcelona 08036, Spain (e-mail: jgon@clinic.ub.es). Prognostic indicators gathered in the early follow-up Copyright r 2007 by Lippincott Williams & Wilkins include early rebleeding, bacterial infection, and renal S312 J Clin Gastroenterol  Volume 41, Supp. 3, November/December 2007
  • 2. J Clin Gastroenterol  Volume 41, Supp. 3, November/December 2007 Acute Variceal Bleeding failure.15 From these data it is clear that management of Change in portal pressure (mmHg) Bleeding bleeding cirrhotic patients should be aimed not only at controlling the bleeding, but also at preventing early 3 rebleeding, infection, and renal failure. transfusion (1:3 blood/expander) as Placebo 2 required to maintain MAP 80 mmHg TREATMENT 1 Acute variceal bleeding should be managed in an 0 intensive care setting by a team of experienced medical 20 ’ 25 ’ 40 ’ Vasopressin staff, including well-trained nurses, clinical hepatologists, analogue endoscopists, interventional radiologists, and surgeons. FIGURE 1. Effects of blood volume replacement on portal Lack of these facilities demands immediate referral. pressure in rats with a portal hypertension-related bleeding. Decision-making shall follow the guidelines set up in a Even by using a conservative target (mean arterial pressure of written protocol developed to optimize the resources of 80 mm Hg) volume replacement induced a rebound increase each center. in portal pressure. This was totally blunted by the use of a vasopressin analog (constructed with data from Ref. 19). General Management The general management of the bleeding patient is Pugh classification) without increasing the incidence of aimed at correcting hypovolemic shock (with judicious adverse events.21 A more recent trial tested rVIIa in volume replacement and transfusion) and at preventing patients with active bleeding at endoscopy and with a complications associated with gastrointestinal bleeding Child-Pugh score Z8 points. This trial failed to show a (bacterial infections, hepatic decompensation, renal benefit of rVIIa in terms of decreasing the risk of 5-day failure), which are independent of the cause of the failure but improved 6-week mortality.22 hemorrhage and demand immediate management. Infection is a strong prognostic indicator in acute Initial resuscitation should follow the classic variceal bleeding.6 The more frequent infections are Airway, Breathing, Circulation scheme, and it is aimed spontaneous bacterial peritonitis (50%), urinary tract at maintaining the aerobic metabolism by restoring an infections (25%), and pneumonia (25%). The use of appropriate delivery of oxygen to the tissues (which antibiotics in acute variceal bleeding has been shown to depends on SaO2, cardiac output, and hemoglobin reduce both the risk of rebleeding23 and mortality.24 concentration). Therefore, antibiotics should be given to all patients from Airway should be immediately secured, especially in admission. Quinolones are frequently used due to its easy encephalopathic patients, because the patient is at risk of administration and low cost.25 In high-risk patients bronchial aspiration of gastric contents and blood. This (hypovolemic shock, ascites, jaundice, or malnutrition) risk is further exacerbated by endoscopic procedures. IV ceftriaxone has recently been shown to be superior to Endotracheal intubation is mandatory if there is any oral norfloxacin.26 concern about the safety of the airway. Blood volume Variceal bleeding can trigger hepatic encephalopa- replacement should be initiated as soon as possible with thy. However, there is no data to support the prophylactic plasma expanders, aiming at maintaining systolic blood use of lactulose or lactitol.2 pressure around 100 mm Hg. Avoiding prolonged hypo- tension is particularly important to prevent infection, Hemostatic Treatments renal failure, and deterioration of liver function which are Initial therapy for acute variceal bleeding is based associated with increased risk of rebleeding and death.15 on the combination of vasoactive drugs with endoscopic Although it has been shown that volume expansion may therapy. Rescue therapies for failures include balloon induce rebound increases in portal pressure and rebleed- tamponade and portal-systemic shunts, either surgical or ing,16,17 the use of vasopressin analogs or somatostatin TIPS. blunt the increase in portal pressure induced by volume expansion18,19 (Fig. 1). Thus, the use of vasoactive drugs Pharmacologic Therapy allows a less conservative blood volume restitution policy. The action of vasoactive drugs is to reduce variceal Blood transfusion should aim at maintaining the hema- pressure by decreasing variceal blood flow. The selection tocrit at 0.21 to 0.24 (Hb 7 to 8 g/L),2 except in patients of the drug depends on the local resources. Terlipressin with rapid ongoing bleeding or with ischemic heart should be the first choice if available, because it is the disease. The role of platelet transfusion or fresh frozen only drug shown to improve survival.3,27 Somatostatin, plasma administration has not been assessed appropri- octreotide, or vapreotide are second choice.3,28 If these ately. The use of recombinant activated factor VII (rVIIa, drugs are not available vasopressin plus transdermal Novoseven), which corrects prothrombin time in cirrho- nitroglycerin is an acceptable option.3 tics,20 has been assessed in 2 randomized controlled trials (RCTs). The first trial showed, in a post hoc analysis, that Terlipressin rFVIIa administration may significantly improve the It is a long-acting triglycyl lysine derivative of results of conventional therapy in patients with moderate vasopressin. Clinical studies have consistently shown less and advanced liver failure (stages B and C of the Child- frequent and severe side effects with terlipressin than with r 2007 Lippincott Williams & Wilkins S313
  • 3. Abraldes and Bosch J Clin Gastroenterol  Volume 41, Supp. 3, November/December 2007 vasopressin, even when vasopressin is associated with of sclerotherapy have shown a significant benefit in terms nitroglycerin. The most common side effect of this drug is of reducing early rebleeding.37 It has been speculated that abdominal pain. Serious side effects such as peripheral or this may be related to its sustained ability to prevent myocardial ischemia occur in <3% of the patients.29 postprandial increase in portal pressure.28 Mortality, Terlipressin may be initiated as early as variceal bleeding however, was not affected.3,37 These results suggest that is suspected at a dose of 2 mg/4 h for the first 48 hours, octreotide may improve the results of endoscopic therapy and it may be maintained for up to 5 days at a dose of but has uncertain effects if used alone. When compared 1 mg/4 h to prevent rebleeding.29 Compared with placebo with other vasoactive drugs, octreotide was better than or nonactive treatment terlipressin significantly improves vasopressin and equivalent to terlipressin, again suggest- the rate of control of bleeding and survival.30 This is the ing a clinical value from the use of octreotide, although all only treatment that has been shown to improve prognosis these studies were underpowered and none was double- of variceal bleeding.3,30 Terlipressin is as effective as any blind.3 other effective therapy, including endoscopic injection sclerotherapy, and is safer than vasopressin+nitrogly- Endoscopic Therapy cerin and endoscopic injection sclerotherapy.3,29,30 The Both sclerotherapy and band ligation [endoscopic overall efficacy of terlipressin in controlling acute variceal band ligation (EBL)] have shown to be effective in the bleeding at 48 hours is of 75% to 80% across trials,30 and control of acute variceal bleeding. Two randomized trials of 67% at 5 days.29 Terlipressin is also useful in specifically compared band ligation and sclerotherapy in hepatorenal syndrome.31 Thus, the use of terlipressin acute variceal bleeding.38,39 In one of them all patients for variceal bleeding may prevent renal failure, which is received also pharmacologic therapy (somatostatin).39 In frequently precipitated by variceal bleeding.15 8 additional trials these 2 modalities were compared both in acute bleeding and in the prevention of rebleeding. Somatostatin Meta-analysis shows that EBL is better than sclerother- It is commonly used as an initial bolus of 250 mg apy in the initial control of bleeding, and is associated followed by a 250 mg/h infusion that is maintained until with less adverse events and improved mortality (Fig. 2). the achievement of a 24 hours bleed-free period. The Additionally, sclerotherapy, but not EBL, may induce a bolus injection can be repeated up to 3 times in the first sustained increase in portal pressure.40 Therefore, EBL hour if bleeding is uncontrolled. Therapy may be further should be the endoscopic therapy of choice in acute maintained for up to 5 days to prevent early rebleeding.32 variceal bleeding, though injection sclerotherapy is The use of higher doses (500 mg/h) cause a greater fall in acceptable if band ligation is not available or technically HVPG and translates into increased clinical efficacy in the difficult. Endoscopic therapy can be performed at the time subset of patients with more difficult bleedings (those with of diagnostic endoscopy, early after admission, provided active bleeding at emergency endoscopy).33 Major side that a skilled endoscopist is available. This is important effects with somatostatin are rare. Minor side effects, such because there has been an increased frequency of as nausea, vomiting, and hyperglycemia occur in up 30% aspiration pneumonia since emergency endoscopic ther- of patients.32–34 Several RCTs showed that somatostatin apy has become universal practice. significantly improves the rate of control of bleeding compared with placebo or nonactive treatment.3,28 How- ever, despite the beneficial effect on control of bleeding, somatostatin did not reduce mortality.3 Somatostatin has Current Recommendations for Initial Treatment been compared with terlipressin and no differences were The current recommendation is to combine these 2 found for failure to control bleeding, rebleeding, mortal- approaches, starting vasoactive drug therapy early ity, or in the incidence of adverse events in both treatment (ideally during the transferal to the hospital, even if groups.3 active bleeding is only suspected) and performing EBL (or injection sclerotherapy if band ligation is technically Octreotide difficult) after initial resuscitation when the patient is It is a somatostatin analog with longer half-life. stable and bleeding has ceased or slowed (Fig. 3). The This, however, is not associated with longer hemody- rationale for that comes from a number of RCTs namic effects than somatostatin.35 The optimal doses are demonstrating that early administration of a vasoactive not well determined. It is usually given as an initial bolus drug facilitates endoscopy and improves control of of 50 mg, followed by an infusion of 25 or 50 mg/h.28 As bleeding and 5-day rebleeding.27,34,41,42 Drug therapy with somatostatin, therapy can be maintained for 5 days also improves the results of endoscopic treatment if to prevent early rebleeding. The safety profile of octreo- started just after sclerotherapy or band ligation.3,37 Vice tide is close to that of somatostatin. The efficacy of versa, the association of endoscopic therapy also im- octreotide as a single therapy for variceal bleeding is proves the efficacy of vasoactive treatment.34 However, controversial. No benefit from octreotide was found in this combined approach failed to significantly improve 6- the only trial using octreotide or placebo as initial week mortality with respect to endoscopic therapy43 or a treatment,36 which may be due to rapid development of vasoactive drug34 alone. The optimal duration of drug tachyphylaxis.35 However, RCTs using octreotide on top therapy is not well established and requires evaluation. S314 r 2007 Lippincott Williams & Wilkins
  • 4. J Clin Gastroenterol  Volume 41, Supp. 3, November/December 2007 Acute Variceal Bleeding 2/14 3/13 0.62 [0.12, 3.13] 2/21 2/23 1.10 [0.17, 7.10] 3/14 0/11 5.60 [0.32, 98.21] 1/9 1/9 1.00 [0.07, 13.64] 1/10 1/12 1.20 [0.09, 16.84] 0/20 2/16 0.16 [0.01, 3.15] 1/18 3/15 0.28 [0.03, 2.40] 1/37 8/34 0.11 [0.02, 0.87] 1/5 1/7 1.40 [0.11, 17.45] 4/90 13/89 0.30 [0.10, 0.90] 238 229 0.47 [0.27, 0.81] 7/37 12/34 0.54 [0.24, 1.20] 12/90 19/89 0.62 [0.32, 1.21] 127 123 0.59 [0.35, 0.98] FIGURE 2. Meta-analysis comparing the efficacy of urgent EBL versus sclerotherapy as initial treatment in variceal bleeding. EBL is more effective for the initial control of bleeding and is associated with less mortality. #All patients received somatostatin. Current recommendation is to maintain the drug for 2 to 5 days, to cover the period of maximum risk of rebleeding.2 Rescue Therapies In 10% to 20% of patients variceal bleeding is unresponsive to initial endoscopic and/or pharmacologic treatment. If bleeding is mild and the patient is stable a second endoscopic therapy (if technically possible) might be attempted. If this fails, or bleeding is severe, the patient should be offered a derivative treatment, before the clinical status of the patient further deteriorates. Balloon tamponade achieves hemostasis in 60% to 90% of variceal bleedings44 but should only be used in the case of a massive bleeding, for a short period of time (<24 h) as a temporal ‘‘bridge’’ until definite treatment is instituted. Bleeding recurs after deflation in over half of the cases and severe complications are common. A recent report suggest that the use of esophageal covered stents might achieve hemostasis in most patients with refractory FIGURE 3. Recommendations for the treatment of acute bleeding,45 with the advantage over tamponade of less bleeding from esophageal varices. severe complications despite much longer periods of r 2007 Lippincott Williams & Wilkins S315
  • 5. Abraldes and Bosch J Clin Gastroenterol  Volume 41, Supp. 3, November/December 2007 treatment. Adequately designed trials should confirm 10. Carbonell N, Pauwels A, Serfaty L, et al. Improved survival after these findings. variceal bleeding in patients with cirrhosis over the past two decades. Both TIPS and surgical shunts are extremely Hepatology. 2004;40:652–659. 11. Chalasani N, Kahi C, Francois F, et al. Improved patient survival effective controlling variceal bleeding (control rate after acute variceal bleeding: a multicenter, cohort study. Am J approaches 95%), but due to worsening of liver function Gastroenterol. 2003;98:653–659. and encephalopathy mortality remains high.44,46 TIPS is 12. Stokkeland K, Brandt L, Ekbom A, et al. Improved prognosis for first choice, because most patients requiring rescue patients hospitalized with esophageal varices in Sweden 1969-2002. Hepatology. 2006;43:500–505. treatment have advanced liver disease. Anyhow, rarely, 13. D’Amico G, Luca A. Natural history. Clinical-haemodynamic if ever, a patient with a Child-Pugh score over 13 will correlations. Prediction of the risk of bleeding. Baillieres Clin survive TIPS. This clearly indicates that some patients do Gastroenterol. 1997;11:243–256. not benefit from TIPS in this setting, and sometimes it is 14. Nidegger D, Ragot S, Berthelemy P, et al. Cirrhosis and bleeding: difficult to make a clinical-based decision. Prognostic the need for very early management. J Hepatol. 2003;39:509–514. 15. Cardenas A, Gines P, Uriz J, et al. Renal failure after upper scores47 may provide objective parameters to ease the gastrointestinal bleeding in cirrhosis: incidence, clinical course, decision of not offering invasive treatments in difficult predictive factors, and short-term prognosis. Hepatology. 2001;34: cases. 671–676. The high mortality associated with the use of TIPS 16. McCormick PA, Jenkins SA, McIntyre N, et al. Why portal as a rescue treatment raises the question on whether hypertensive varices bleed and bleed: a hypothesis. Gut. 1995; 36:100–103. patients with poor prognostic indicators might benefit 17. Castaneda B, Debernardi-Venon W, Bandi JC, et al. The role of from a more aggressive therapeutic approach ab initio. portal pressure in the severity of bleeding in portal hypertensive rats. This was recently explored in a randomized trial in which Hepatology. 2000;31:581–586. patients with high portal pressure (>20 mm Hg) were 18. Villanueva C, Ortiz J, Minana J, et al. Somatostatin treatment and randomized to receive standard therapy or TIPS. Those risk stratification by continuous portal pressure monitoring during acute variceal bleeding. Gastroenterology. 2001;121:110–117. who underwent early TIPS had significantly less treat- 19. Morales J, Moitinho E, Abraldes JG, et al. Effects of the V1a ment failure and lower mortality than patients under- vasopressin agonist F-180 on portal hypertension-related bleeding in going standard therapy.9 However, the standard therapy portal hypertensive rats. Hepatology. 2003;38:1378–1383. used in the control arm of this trial was only endoscopic 20. Ejlersen E, Melsen T, Ingerslev J, et al. Recombinant activated therapy, which is not the current standard of combination factor VII (rFVIIa) acutely normalizes prothrombin time in patients with cirrhosis during bleeding from oesophageal varices. Scand J of vasoactive drugs for 2 to 5 days and endoscopic Gastroenterol. 2001;36:1081–1085. treatment.2 An ongoing multicenter study will answer 21. Bosch J, Thabut D, Bendtsen F, et al. Recombinant factor VIIa whether early TIPS (performed with covered stents) is for upper gastrointestinal bleeding in patients with cirrhosis: superior to combination therapy in high-risk patients a randomized, double-blind trial. Gastroenterology. 2004;127: (ISRCTN58150114). 1123–1130. 22. Bosch J, Thabut D, Albillos A, et al. Recombinant factor VIIA (RFVIIA) for active variceal bleeding in patients with advanced REFERENCES cirrhosis: a multi-centre randomized double-blind placebo-con- 1. D’Amico G, de Franchis R. Upper digestive bleeding in cirrhosis. trolled trial. J Hepatol. 2007;46(suppl 1):295A. Post-therapeutic outcome and prognostic indicators. Hepatology. 23. Hou MC, Lin HC, Liu TT, et al. Antibiotic prophylaxis after 2003;38:599–612. endoscopic therapy prevents rebleeding in acute variceal hemor- 2. de Franchis R. Evolving Consensus in Portal Hypertension Report rhage: a randomized trial. Hepatology. 2004;39:746–753. of the Baveno IV Consensus Workshop on methodology of 24. Bernard B, Grange JD, Khac EN, et al. Antibiotic prophylaxis for diagnosis and therapy in portal hypertension. 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