Management of gastrointestinal bleeding in patients with cirrhosis of the liver

Management of Gastrointestinal Bleeding in Patients With Cirrhosis of the Liver Jaime Bosch and Juan G. Abraldes Ruptured gastroesophageal varices are the most severe and frequent cause of gastrointestinal bleeding in cirrhotic patients, leading to death in 5% to 8% of patients during the first 48 hours. In recent times, the 6-week mortality rate has fallen to 20% due to the development of effective treatment strategies. Initial treatment is aimed at achieving hemostasis and preventing bleeding-related complications such as renal failure, infection, and hepatic decompensation. Blood volume replacement is initiated as soon as possible and antibiotic prophylaxis is instituted from admission. Hemostatic treatment for variceal bleeding includes vasoactive drugs to decrease portal pressure, endoscopic procedures, and portosystemic shunts— either a surgical or transjugular intrahepatic portosystemic shunt (TIPS). Treatment of coagulopathy has only been recently assessed in clinical studies, but results to date are promising. This article reviews the current clinical data on management strategies for variceal bleeding and presents the risks and benefits for each type of treatment. Specific sections on gastric varices and portal hypertensive gastropathy are included. Semin Hematol 41(suppl 1):8-12. © 2004 Elsevier Inc. All rights reserved.

M

ASSIVE GASTROINTESTINAL bleeding is one of the more frequent and severe complications of cirrhosis. Although cirrhotic patients may bleed from various locations, ruptured gastroesophageal varices are the most severe and frequent cause of gastrointestinal bleeding in these patients, accounting for 80% of the bleeding episodes.17 Variceal bleeding is often very severe, with about 5% to 8% of patients dying within 48 hours from uncontrolled bleeding.2,25 Active bleeding at emergency endoscopy,8 bacterial infection,27 and hepatic venous pressure gradient (HVPG) greater than 20 mm Hg measured early after admission37 are significant prognostic indicators of failure to control bleeding. These factors, together with low albumin and renal failure, are also significant prognostic indicators of early rebleeding risk.25 Following the initial bleed, the incidence of early rebleeding within the first 6 weeks ranges from 30% to 40%.2 The risk peaks in the first 5 days, during which 40% of all rebleeding episodes occur28; such early rebleeding carries poor prognosis. According to international consensus,23,47 mortality in variceal bleeding is now assessed at 6 weeks. Earlier studies suggested that the mortality rate was approximately 30% to 50%; however, with the develFrom the Liver Unit, IMD, Hospital Clı´nic, IDIBAPS, University of Barcelona, Barcelona, Spain. Supported in part by a grant from the Instituto de Salud Carlos III (CO3/O2). Address correspondence to Professor Jaime Bosch, Hospital Clinic, C/ Villarroel 170, 08036 Barcelona, Spain. © 2004 Elsevier Inc. All rights reserved. 0037-1963/04/4101-1002$30.00/0 doi:10.1053/j.seminhematol.2003.11.003

8

opment of effective treatment, the current rate of mortality has decreased to 20%.36 The most important death risk indicators appear to be the severity of liver disease, renal failure, and persistence and recurrence of the bleed.3

Pathophysiology of Variceal Bleeding Variceal bleeding is the last step in a sequence of events initiated by increased portal pressure and followed by the development and progressive dilation of varices, until bleeding occurs (Fig 1). The pressure gradient in any vascular system depends on the relationship between the flow within the system and the resistance opposing the flow. According to Ohm’s law the portal pressure gradient (PPG) can be defined as: PPG ⫽ blood flow ⫻ resistance. Changes in portal pressure are, therefore, influenced by changes in flow and resistance in the portal venous system, which includes the portal vein, the portocollateral circulation, and the intrahepatic circulation. Many studies have shown that the initial factor leading to portal hypertension in cirrhosis is an increase in hepatic resistance.13,52 As the portal pressure rises above normal values, collateral circulation develops in an attempt to decompress the portal system. Gastroesophageal varices represent the most common and clinically relevant type of collaterals. Collateralization of the portal system is accompanied by splanchnic vasodilatation and a resultant increase in portal venous inflow. This represents an important factor contributing to the maintenance and worsening of the increase in portal pressure.13 A threshold increase in the PPG (most commonly evaluated in clinical practice by measuring the HVPG) is necessary for the development of esopha-

Seminars in Hematology, Vol 41, No 1, Suppl 1 ( January), 2004: pp 8-12

Medical Treatment of Variceal Bleeding

Figure 1.

Pathophysiology of variceal formation and rupture.

geal varices; values over 12 mm Hg represent “clinically significant portal hypertension.”26,50 Variceal bleeding does not occur if HVPG does not reach 12 mm Hg or if it decreases below this value.22,29 However, once varices have developed, their dimensions tend to increase, increasing the risk of bleeding. At present, the “explosion” hypothesis is the most widely accepted to explain variceal rupture.43 This idea suggests that increased hydrostatic pressure inside the varix is the main factor implicated in variceal rupture, contributing to increases in variceal size and decreases in the thickness of its wall. Variceal bleeding is thought to occur when the tension exerted by the thin wall of the varix exceeds a critical value, determined by the elastic limit of the vessel. According to Frank’s modification of Laplace’s law, variceal wall tension is directly proportional to the transmural variceal pressure (the gradient between variceal and intraesophageal pressures) and the radius of the varix, and inversely proportional to the thickness of the variceal wall. This pathophysiological concept supports the clinical observations that increased variceal pressure, increased variceal size, and presence of the so-called “red-color signs” (markers of reduced wall thickness) are independent predictors of the risk of variceal bleeding.25 Indeed, a recent hemodynamic study showed the relevance of portal pressure in the outcome of acute variceal bleeding.37 In this study, patients with an admission HVPG ⱖ 20 mm Hg (40% of the total population) had a much worse outcome than patients with HVPG ⬍ 2 mm Hg, as shown by a significantly higher frequency of uncontrolled bleeding, early rebleeding, 1-year mortality, and transfusion requirements, along with a greater length of stay in intensive care and increased total hospital stay.

9

care setting by a team of experienced medical staff, including well-trained nurses, clinical hepatologists, endoscopists, an interventional radiologist, and surgeons. If these facilities are not available, then the patient should be immediately referred. Decisionmaking should follow the guidelines outlined in the center protocol, which is developed to optimize resources and improve outcome. As mentioned above, the most important prognostic factors in variceal bleeding are the severity of liver disease, infection, renal failure, and persistence and early recurrence of the bleed.3 Therefore, initial therapy should be aimed both at achieving hemostasis at the bleeding site and at preventing bleeding-related complications such as renal failure, infection and hepatic decompensation. The latter is independent of the cause of the hemorrhage and demands immediate management. Specific therapy to stop bleeding is usually given following initial resuscitation and diagnostic endoscopy, but pharmacological therapy can be started earlier in the course of the bleeding episode (Fig 2).

General Management Blood volume replacement should be initiated as soon as possible with the aim of maintaining the hematocrit between 25% and 30%. The avoidance of prolonged hypovolemic shock is particularly important to prevent complications such as infection and renal failure, which are associated with the risk of rebleeding and death.17,25 Overtransfusion, however, should be avoided, not only because of the risks inherent with blood transfusion, but also because there may be a rebound increase in portal pressure and a consequent risk of continued bleeding or subsequent rebleeding.18,35 Antibiotic prophylaxis should be instituted from admission since early administration has been shown to improve survival in episodes of acute variceal bleeding.9 Oral norfloxacin is the drug of choice due to its simple mode of administration and low cost.45 The presence of infection should be subsequently investigated. Since bronchial aspiration of gastric contents and

Management Variceal bleeding is a medical emergency and its management should be undertaken in an intensive

Figure 2. Management of acute variceal bleeding. Rx, therapy; TIPS, transjugular intrahepatic portosystemic shunt; EVS, endoscopic variceal sclerotherapy.

10

Bosch and Abraldes

blood is a particular problem, especially in encephalopathic patients, and since it may be further exacerbated by endoscopic procedures, endotracheal intubation is mandatory if there are any concerns about the safety of the airway. The role of coagulopathy in the outcome of acute variceal bleeding, and the possible beneficial effects of its correction have only been recently assessed in clinical studies. Initial reports demonstrate that recombinant activated factor VII (rFVIIa; NovoSeven威, Novo Nordisk, Bagsvaerd, Denmark) corrects prothrombin time in cirrhotics, both in nonbleeders10 and in the acute variceal bleeding setting.21 Furthermore, preliminary results of a very recent doubleblind, randomized, controlled, multicenter trial suggest that rFVIIa administration significantly improves the outcome with conventional therapy in a subgroup of patients with moderate and advanced liver failure (stages B and C of the Child-Pugh classification), in whom variceal bleeding carries a more severe prognosis. There was no increase in the incidence of adverse events in this study.48 These results must be confirmed in other trials focusing on this target population. Recombinant FVIIa may also prove useful in patients with uncontrolled bleeding or with very early rebleeding.

Specific Treatment for Variceal Bleeding Hemostatic treatment for variceal bleeding includes vasoactive drugs to decrease portal pressure, endoscopic procedures and portosystemic shunts, either surgical or with a transjugular intrahepatic portosystemic shunt (TIPS).3,15,24 The current recommendations for hemostatic treatment are to initiate a vasoactive drug upon admission, and to undertake endoscopic therapy at the time of diagnostic endoscopy.14,23 The drug treatment may be started during transfer to hospital by medical or paramedical teams33 and maintained for up to 5 days in order to prevent early rebleeding.23 This approach provides an initial control of bleeding with a success rate of approximately 75%. The rationale for combined treatment comes from a number of randomized, controlled trials demonstrating that the early administration of a vasoactive drug facilitates endoscopy and improves control of bleeding and 5-day rebleeding.6,16,33 Drug therapy still improves the results of endoscopic treatment if started just after sclerotherapy or band ligation1,3,20 and it appears that concomitant endoscopic therapy improves the efficacy of vasoactive treatment alone, both in low- and high-risk patients.51 However, as in most trials undertaken in acute variceal bleeding, this combined approach failed to improve 6-week mortality with respect to endoscopic therapy7 or vasoactive drug51 alone. Conversely, single vasoactive drug therapy is as effective as endoscopic therapy, but with signifi-

cantly fewer side effects,5 which raises questions about the use of endoscopic therapy as single treatment. The selection of vasoactive drug therapy often depends on the local resources. Terlipressin should be the first choice if available, since it is the only vasoactive drug shown to improve survival.33 Somatostatin or octreotide are second choices,1,3 and if these drugs are not available, vasopressin plus transdermal nitroglycerin is an acceptable option.3 Regarding endoscopic therapy in the acute bleeding episode, either sclerotherapy or band ligation may be used.24 The former avoids repeated intubation, but the latter carries a lower risk of local complications. If early recurrent bleeding occurs, a single endoscopic re-treatment may be offered if bleeding is mild and does not compromise the patient. Otherwise, the patient should be sent for derivative treatment. In the case of a massive bleed, a balloon tamponade with the Sengstaken-Blakemore tube (for esophageal varices) or with the Linton-Nachlas tube (for gastric varices) can be used as a bridge until derivative treatment is instituted. Both TIPS and surgical shunts are extremely effective at controlling variceal bleeding (control rate approaches 95%), but invasiveness and side effects (mainly encephalopathy and worsening of liver function) result in high mortality.4,11,15 TIPS is the treatment of choice, since most patients have advanced liver disease that is associated with a high operative mortality.30 Shunt surgery, preferably an H-graft meso-caval shunt, may be an alternative option in Child A patients if an experienced surgeon is available.

Gastric Varices The optimal treatment for patients bleeding from gastric varices (5% to 10% of upper digestive bleeding episodes in patients with cirrhosis) remains controversial. The common approach is to initiate a vasoactive drug12; if the bleeding is not controlled, endoscopic treatment with cyanoacrylate can be attempted by an expert endoscopist.34,46 In the case of massive bleeding or after failure of previous therapies, TIPS (or surgical shunt in Child A patients) is mandatory.19 These patients merit an earlier decision for TIPS than patients bleeding from esophageal varices and, in some cases, TIPS may be used even before attempting endoscopic therapy.

Portal Hypertensive Gastropathy Portal hypertensive gastropathy (PHG) is present in around 80% of cirrhotic patients, but constitutes an uncommon cause of acute gastrointestinal bleeding.44 Propranolol, somatostatin, octreotide, vasopressin, terlipressin, and estrogens have been proposed for the treatment of PHG based on their ability

Medical Treatment of Variceal Bleeding

to decrease gastric perfusion in this condition.39-42 However, only a single uncontrolled study has so far demonstrated the benefit of one of these drugs (somatostatin) in the treatment of acute bleeding from PHG with the achievement of hemostasis in all patients.32 Reported results with shunt surgery and TIPS suggest that these treatments are effective,31,38,49 but due to lack of randomized studies, the fluctuating nature of PHG and, possibly, to unreported failures, both TIPS and shunt surgery should be considered only as rescue therapies.

18.

19.

20.

21.

References 1. Abraldes JG, Bosch J: Somatostatin and analogues in portal hypertension. Hepatology 35:1305-1312, 2002 2. D’Amico G, Luca A: Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding. Baillieres Clin Gastroenterol 11:243-256, 1997 3. D’Amico G, Pagliaro L, Bosch J: Pharmacological treatment of portal hypertension: An evidence-based approach. Semin Liver Dis 19:475-505(erratum 20:399, 2000), 1999 4. D’Amico G, Pagliaro L, Bosch J: The treatment of portal hypertension: A meta-analytic review. Hepatology 22:332354, 1995 5. D’Amico G, Pietrosi G, Tarantino I, et al: Emergency sclerotherapy versus medical interventions for bleeding oesophageal varices in cirrhotic patients. Cochrane Database Syst Rev 1:CD002233, 2002 6. Avgerinos A, Nevens F, Raptis S, et al: Early administration of somatostatin and efficacy of sclerotherapy in acute oesophageal variceal bleeds: The European Acute Bleeding Oesophageal Variceal Episodes (ABOVE) randomised trial. Lancet 350:1495-1499, 1997 7. Banares R, Albillos A, Rincon D, et al: Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology 35:609-615, 2002 8. Ben-Ari Z, Cardin F, McCormick AP, et al: A predictive model for failure to control bleeding during acute variceal haemorrhage. J Hepatol 31:443-450, 1999 9. Bernard B, Grange JD, Khac EN, et al: Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: A meta-analysis. Hepatology 29:1655-1661, 1999 10. Bernstein DE, Jeffers L, Erhardtsen E, et al: Recombinant factor VIIa corrects prothrombin time in cirrhotic patients: A preliminary study. Gastroenterology 113:1930-1937, 1997 11. Bosch J: Salvage transjugular intrahepatic portosystemic shunt: Is it really life-saving? J Hepatol 35:658-660, 2001 12. Bosch J, Abraldes JG, Groszmann R: Current management of portal hypertension. J Hepatol 38:S54-S68, 2003 (suppl) 13. Bosch J, Garcia-Pagan JC: Complications of cirrhosis. I. Portal hypertension. J Hepatol 32:141-156, 2000 (suppl) 14. Burroughs AK, Patch DW: Management of variceal haemorrhage in cirrhotic patients. Gut 48:738-740, 2001 15. Burroughs AK, Patch D: Transjugular intrahepatic portosystemic shunt. Semin Liver Dis 19:457-473, 1999 16. Cales P, Masliah C, Bernard B, et al: Early administration of vapreotide for variceal bleeding in patients with cirrhosis. French Club for the Study of Portal Hypertension. N Engl J Med 344:23-28, 2001 17. Cardenas A, Gines P, Uriz J, et al: Renal failure after upper gastrointestinal bleeding in cirrhosis: Incidence, clinical

22.

23.

24. 25.

26.

27.

28. 29.

30. 31.

32.

33.

34.

35.

36.

37.

11

course, predictive factors, and short-term prognosis. Hepatology 34:671-676, 2001 Castaneda B, Debernardi-Venon W, Bandi JC, et al: The role of portal pressure in the severity of bleeding in portal hypertensive rats. Hepatology 31:581-586, 2000 Chau TN, Patch D, Chan YW, et al: “Salvage” transjugular intrahepatic portosystemic shunts: gastric fundal compared with esophageal variceal bleeding. Gastroenterology 114:981-987, 1998 Corley DA, Cello JP, Adkisson W, et al: Octreotide for acute esophageal variceal bleeding: A meta-analysis. Gastroenterology 120:946-954, 2001 Ejlersen E, Melsen T, Ingerslev J, et al: Recombinant activated factor VII (rFVIIa) acutely normalizes prothrombin time in patients with cirrhosis during bleeding from oesophageal varices. Scand J Gastroenterol 36:1081-1085, 2001 Feu F, Garcia-Pagan JC, Bosch J, et al: Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet 346:1056-1059, 1995 de Franchis R: Updating consensus in portal hypertension: Report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 33:846-852, 2000 de Franchis R, Primignani M: Endoscopic treatments for portal hypertension. Semin Liver Dis 19:439-455, 1999 de Franchis R, Primignani M: Natural history of portal hypertension in patients with cirrhosis. Clin Liver Dis 5:645-663, 2001 Garcia-Tsao G, Groszmann RJ, Fisher RL, et al: Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 5:419-424, 1985 Goulis J, Armonis A, Patch D, et al: Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 27:1207-1212, 1998 Graham DY, Smith JL: The course of patients after variceal hemorrhage. Gastroenterology 80:800-809, 1981 Groszmann RJ, Bosch J, Grace ND, et al: Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 99:1401-1407, 1990 Henderson JM: Salvage therapies for refractory variceal hemorrhage. Clin Liver Dis 5:709-725, 2001 Kamath PS, Lacerda M, Ahlquist DA, et al: Gastric mucosal responses to intrahepatic portosystemic shunting in patients with cirrhosis. Gastroenterology 118:905-911, 2000 Kouroumalis EA, Koutroubakis IE, Manousos ON: Somatostatin for acute severe bleeding from portal hypertensive gastropathy. Eur J Gastroenterol Hepatol 10:509-512, 1998 Levacher S, Letoumelin P, Pateron D, et al: Early administration of terlipressin plus glyceryl trinitrate to control active upper gastrointestinal bleeding in cirrhotic patients. Lancet 346:865-868, 1995 Lo GH, Lai KH, Cheng JS, et al: A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices. Hepatology 33: 1060-1064, 2001 McCormick PA, Jenkins SA, McIntyre N, et al: Why portal hypertensive varices bleed and bleed: A hypothesis. Gut 36: 100-103, 1995 McCormick PA, O’Keefe C: Improving prognosis following a first variceal haemorrhage over four decades. Gut 49:682685, 2001 Moitinho E, Escorsell A, Bandi JC, et al: Prognostic value of

12

38.

39.

40.

41.

42.

43.

44.

45.

Bosch and Abraldes

early measurements of portal pressure in acute variceal bleeding. Gastroenterology 117:626-631, 1999 Orloff MJ, Orloff MS, Orloff SL, et al: Treatment of bleeding from portal hypertensive gastropathy by portacaval shunt. Hepatology 21:1011-1017, 1995 Panes J, Bordas JM, Pique JM, et al: Effects of propranolol on gastric mucosal perfusion in cirrhotic patients with portal hypertensive gastropathy. Hepatology 17:213-218, 1993 Panes J, Casadevall M, Fernandez M, et al: Gastric microcirculatory changes of portal-hypertensive rats can be attenuated by long-term estrogen-progestagen treatment. Hepatology 20:1261-1270, 1994 Panes J, Pique JM, Bordas JM, et al: Effect of bolus injection and continuous infusion of somatostatin on gastric perfusion in cirrhotic patients with portal-hypertensive gastropathy. Hepatology 20:336-341, 1994 Panes J, Pique JM, Bordas JM, et al: Reduction of gastric hyperemia by glypressin and vasopressin administration in cirrhotic patients with portal hypertensive gastropathy. Hepatology 19:55-60, 1994 Polio J, Groszmann RJ: Hemodynamic factors involved in the development and rupture of esophageal varices: A pathophysiologic approach to treatment. Semin Liver Dis 6:318-331, 1986 Primignani M, Carpinelli L, Preatoni P, et al: Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC). Gastroenterology 119:181-187, 2000 Rimola A, Garcia-Tsao G, Navasa M, et al: Diagnosis, treat-

46.

47.

48.

49.

50.

51.

52.

ment and prophylaxis of spontaneous bacterial peritonitis: A consensus document. International Ascites Club. J Hepatol 32:142-153, 2000 Sarin SK, Jain AK, Jain M, et al: A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices. Am J Gastroenterol 97:1010-1015, 2002 Shah V, Garcia-Cardena G, Sessa WC, et al: The hepatic circulation in health and disease: Report of a single-topic symposium. Hepatology 27:279-288, 1998 Thabur D, de Franchis R, Bendtsen F, et al: Efficacy of activated recombinant factor VII (rFVIIa; Novoseven威) in cirrhotic patients with upper gastrointestinal bleeding: A randomised placebo-controlled double-blind multicenter trial. J Hepatol 38:13A, 2003 (suppl, abstr) Urata J, Yamashita Y, Tsuchigame T, et al: The effects of transjugular intrahepatic portosystemic shunt on portal hypertensive gastropathy. J Gastroenterol Hepatol 13:10611067, 1998 Viallet A, Marleau D, Huet M, et al: Hemodynamic evaluation of patients with intrahepatic portal hypertension. Relationship between bleeding varices and the portohepatic gradient. Gastroenterology 69:1297-1300, 1975 Villanueva C, Ortiz J, Sabat M, et al: Somatostatin alone or combined with emergency sclerotherapy in the treatment of acute esophageal variceal bleeding: A prospective randomized trial. Hepatology 30:384-389, 1999 Wiest R, Groszmann RJ: Nitric oxide and portal hypertension: its role in the regulation of intrahepatic and splanchnic vascular resistance. Semin Liver Dis 19:411-426, 1999