MANAGEMENT OF OESOPHAGEAL VARICEAL BLEEDING

Dr. Rosmawati Mohamed,
Dr. Jason Chin,
Dr. Robert Ding,
Dr. Ryan Ponnudurai,
Dr. Sharmila Sachithanandan,
Dr. Harjit Singh, Dr. Tan Soon Seng

Oesophageal variceal bleeding accounts for 6.4% of upper gastrointestinal bleeding in Malaysia1. At the time of diagnosis of cirrhosis, oesophageal varices are present in about 60% of decompensated and 30% of compensated patients2. Despite the high occurrence of varices in cirrhotic patients, only 30% of patients with varices will experience variceal haemorrhage3-4. Mortality of the first bleeding episode is high and ranges between 30% to 50% within 6 weeks5. Patients who survived the first bleed from oesophageal varices are at a significant risk of recurrent haemorrhage: 70% of patients will experience recurrent haemorrhage and about a third of further bleeding episodes are fatal3,6.

Amongst the various classifications of oesophageal varices, the grading developed in Japanese studies is preferred7-8. Varices increase in size from small to large at an annual rate of 10-15%9.

Table 1: Size classifications of oesophageal varices

Japanese
US
VA Trial
Paquet
Absent
Absent
Absent
Absent
Grade 1: small, straight varices not disappearing with insufflation
Small
<5mm
I
Grade 2: medium varices occupying less than one third of the lumen
Medium
5-9mm
II
Grade 3: large varices occupying more than one third of the lumen
Large
>9mm
III
 
Giant
IV

MANAGEMENT OF ACUTE OESOPHAGEAL VARICEAL HAEMORRHAGE

Therapy is aimed at correcting hypovolumic shock and at achieving haemostasis at the bleeding site. Two large bore intravenous lines should be in place. Fluids, preferably packed red blood cells should be transfused to keep the haemoglobin ideally around 10g/dL. Prophylactic antibiotic is generally recommended, because of the high probability of cirrhotic patients to develop infections. Pharmacotherapy to reduce portal pressure should be instituted and emergency endoscopy performed to establish the diagnosis and location of the bleeding site. Balloon tamponade should be considered if facilities for endoscopy are not available prior to transfer to a tertiary centre or if haemostasis has not been achieved.

Vasoactive drugs have been shown to control acute variceal bleeding in about 80% of patients10-14. The selection of the vasoactive drug is highly dependent on availability and the treating clinician's familiarity with each. Terlipressin is preferred as it is the only drug which has been shown to improve survival15. Terlipressin is administered as IV injection of 2 mg bolus and 1 mg every four to six hours for 48 hours. Drug therapy should be maintained for at least 48 hours; 5 days of therapy is recommended for somatostatin and its synthetic analogues, octreotide, to prevent early rebleeding. Somatostatin is given as an IV 250ug bolus followed by 250ug/hour infusion. Octreotide is administered as a bolus injection of 50mcg followed by an infusion at a rate of 50mcg per hour.

Endoscopic therapy effectively controls acute esophageal variceal bleedings16. Randomised controlled trials comparing endoscopic variceal ligation (EVL) and endoscopic sclerotherapy have shown that endoscopic variceal band ligation is similar to sclerotherapy in achieving initial hemostasisis16-19. The combination of a vasoactive agent and endoscopic therapy is recommended as it has been shown to facilitate endoscopy, improve control of bleeding, reduce 5-day rebleeding rate and transfusion requirements20-23.

Transjugular intrahepatic portasystemic shunts (TIPS) is effective in the treatment of acute variceal bleeding with a success rate of over 90% in arresting haemorrhage24,25. The most widely accepted indication for TIPS is as a rescue therapy for uncontrolled variceal bleeding.

Similar to TIPS, the role of surgical therapy in the management of acute variceal bleed has been relegated to salvage haemostatic therapy.

SECONDARY PROPHYLAXIS

Secondary prophylaxis is the prevention of recurrent bleeding after a first episode. Beta-blockers are the mainstay of pharmacotherapy26-28. A meta-analysis of 12 randomized controlled trials comparing nonselective beta-blockers to either no treatment or placebo showed a statistically significant reduction in the risk of recurrent bleeding and survival advantage29. Although the addition of isosorbide mononitrate to beta-blockers for secondary prophylaxis appears to be superior to beta-blocker monotherapy in the prevention of variceal rebleeding, survival benefit was not demonstrated30.

Endoscopic variceal band ligation has superseded sclerotherapy in the prevention of recurrent esophageal variceal hemorrhage because the risk of rebleeding is lower, it causes fewer complications, requires fewer sessions to eradicate the varices and has a survival benefit17,31-34. EVL is performed every 10 to 14 days until the varices are eradicated, which usually takes three or four sessions. The addition of sclerotherapy to ligation has not been shown to be advantageous35,36.

Comparison of beta-blockers and isosorbide mononitrate with endoscopic variceal band ligation revealed either no significant difference in the variceal rebleeding episodes or in survival37,38, significantly less variceal rebleeding but a higher death rate in the EVL group39, or a higher variceal rebleeding rate in the EVL group as compared with pharmacological therapy40. However, pharmacological therapy was found to be effective largely in patients with Child-Pugh A cirrhosis. Noteworthy, the risk of recurrent bleeding and of death was significantly lower in patients who had a hemodynamic response to therapy (defined as a reduction in the hepatic venous pressure gradient by more than 20 percent of the base-line value or to less than 12 mm Hg).

The combination of EVL plus beta-adrenergic blockers and sucralfate was compared with EVL alone41. Triple therapy proved more effective in terms of prevention of variceal rebleeding: however, no significant difference in death rate was identified. Combination therapy involving endoscopic varicael ligation and beta-adrenergic blockers warrants additional investigation.

Although TIPS is more effective than endoscopic therapy for the prevention of variceal rebleeding, TIPS is associated with the occurrence of hepatic encephalopathy in at least 25 percent of patients after the procedure42,43, lacks survival benefit over endoscopic therapy44-46, is more costly than pharmacological therapy47. Secondary prophylaxis with TIPS or surgical shunts are preferred for patients who are noncomp!iant with pharmacological or endoscopic therapy. TIPS is most suited for patients with Child's B or C cirrhosis, particularly those who are candidates for liver transplantation while surgical shunts should be limited to patients with Child's A cirrhosis48. Those with endstage liver disease should be considered for liver transplantation.

RECOMMENDATIONS
The strength of each recommendation are graded as follows49,50:
Grading Of Recommendations
Grade A
Evidence from large, randomised clinical trials or meta-analyses
Grade B
Evidence from high quality studies of well designed, cohorts or case controlled studies
Grade C
Opinions from experts based on arguments from physiology bench research or first principles

RECOMMENDATIONS: MANAGEMENT OF ACUTE OESOFHAGEAL VARICEAL BLEEDING

Resuscitation
Haemodynamic monitoring
At least 2 large bore IV lines should be inserted
Blood - group and crossmatched
Correct coagulopathy
Central venous access
Consider intubation for airway protection if severe uncontrollable bleeding, encephalopathic, inability to maintain oxygen saturation adequately and to prevent aspiration
ICU bed and facilites should be made available

Institute pharmacotherapy
Terlipressin / Octreotide / Somatostatin
(Recommendation grade A)
Therapy should be continued for at least for 48h; 5-day therapy is recommended to prevent early rebleeding.

Antibiotic prophylaxis (Recommendation grade A)
norfloxacin/ciprofloxacin/third generation cephalosporins Antibiotic treatment should be continued for 7 days

Upper Gl Endoscopy
As soon as patient is haemodynamically stable
If endoscopy unavailable, consider balloon tamponade and referral to tertiary centre (Recommendation grade B)

Control of Bleeding
Endoscopic variceal ligation or endoscopic sclerotherapy (Recommendation grade A)

If failure to control bleeding, consider repeating endoscopy
Surgical intervention or TIPS should be considered if failure to control bleeding (Recommendation grade A)

Secondary Prophylaxis
Lifelong non-selective beta-blockers (Recommendation grade A)

Endoscopic variceal ligation if noncompliant, intolerant, contraindications or refractory to beta-blockers (Recomendation grade A)

The combination of beta blockers and EVL if refractory to pharmacological or endoscopic therapy (Recommendation grade A)
TIPS or shunt surgery if noncompliant or refractory to pharmacological and/or endoscopic therapy (Recommendation grade A)

TIPS is most suited for patients with Child's B or C cirrhosis, particularly those who are candidates for liver transplantation while surgical shunts should be limited to patients with Child's A cirrhosis. Those with endstage liver disease should be considered for liver transplantation.

REFERENCES
1. Cheng JLS, Gunn A, Menon J, Arokiasamy J, Ong P, Loong SY, Oommen G. Damodaran A. Aetiology of Acute Upper Gastrointestinal Bleeding in East Malaysia. Med J Mal. 2001; 56 (supp A) D31
2. Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension. A meta-analytic review. Hepatology 1995; 22:332-54.
3. The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices: a prospective mullirenler study. N Engl J Med 1988; 319:983-9.
4. 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 1990; 99:1401-7.
5. Graham DY, Smith JL The course of patients after variceal hemorrhage. Gastroenterology 1981; 80:800-9.
6. de Franchis R, Primignani M. Why do varices bleed? Gastroenterol Clin North Am. 1992; 2:85-101.
7. Reppu K, Inokuchi K, Koyanagi N, et al. Prediction of variceal hemorrhage by esophageal endoscopy. Gastrointest Endosc 1981; 27:213-8.
8. Endo M, Fujita R. Panel discussion. Esophageal varices and endoscopy. Gastrointest Endosc 1983; 25:1827-61.
9. G. D'Amico, L. Peigliaro, J. Bosch, Pharmacological treatment of portal hypertension: an evidence-based approach, Semin Liver Dis 19 (1999) 475-505
10. Kraveb D, Bosch J, Teres J, et al. Comparison of intravenous somatostatin and vasopressin infusions in treatment of acute variceal hemorrhage. Hepatology. 1984 May-Jun;4(3):442-6.
11. Jenkins SA, Baxter JN, Corbett W, et al. A prospective randomised controlled clinical trial comparing somatostatin and vasopressin in controlling acute variceal haemorrhage. Br Med J (Clin Res Ed). 1985 Jan 26; 290(6464):275-8.
12. Bagarani M, Albertini V, Anza M, Effect of somatostatin in controlling bleeding from esophageal varices. Ital J Surg Sci. 1987;17(1):21-6.
13. Saari A, Klvilaakso E, Inberg M, et al. Comparison of somatostatin and vasopressin in bleeding esophageal varices. Am J Gastroenterol. 1990 Jul;85(7):804-7.
14. Hwang SJ, Lin HC, Chang CF, et al. A randomized controlled trial comparing octreotide and vasopressin in the control of acute esophageal variceal bleeding. J Hepatol. 1992 Nov; 16(3):320-5.
15. loannou G, Doust J, Rockey DC. Terlipressin for acute esophageal variceal hemorrhage. Cochrane Database Syst Rev 2003; (1):CD002147
16. Gross M, Schiemann U, Muhlhofer A, Zoller WG. Meta-analysis: efficacy of therapeutic regimens in ongoing variceal bleeding. Endoscopy 2001 Sep; 33(9):737-46
17. Laine L, el-Newihi HM, Migikovsky B, Sloane R, Garcia F. Endoscopic ligation compared with sclerotherapy for the treatment of bleeding esophageal varices. Ann Intern Med 1993; 119:1-7.
18. Lo GH, Lai KH, Cheng JS, et al. Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology 1997; 25:1101-4.
19. Stiegmann GV, Goff JS, Michaletz-Onody PA, et al. Endoscopic sclerotherapy
as compared with endoscopic ligation for bleeding esophageal varices. N Engl J Med 1992; 326:1527-32.
20. Avgerinos, F. Nevens, S. Raptis, J. Fevery, 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 (1997) 1495-1499
21. P. Cales, C. Masliah, B. Bernard, P.P. Gamier, C. Silvain, N. Szostak-Talbodec 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 (2001) 23-28
22. Besson I, Ingrand P, Person B, et al. Sclerotherapy with or without octreotide for acute variceal bleeding. N Engl J Med 1995; 333:555-60.
23. Sung JJ, Chung SC, Yung MY, el al. Prospective randomised study of effect of octreotide on rebleeding from oesophageal varices after endoscopic ligation. Lancet 1995; 346:1666-9.
24. Jalan R, John TG, Redhead DM, et al. A comparative study of emergency transjugular intrahepatic portosystemic stent-shunt and esophageal transection in the management of uncontrolled variceal hemorrhage. Am J Gastroenterol 1995; 90:1932-7.
25. Sanyal AJ, Freedman AM, Luketic VA, et al. Transjugular intrahepatic portosystemic shunts for patients with active variceal hemorrhage unresponsive to sclerotherapy. Gastroenterology 1996, 111:1 38-46
26. Burroughs AK, Jenkins WJ, Sherlock S, et al. Controlled trial of propranolol for the prevention of recurrent variceal hemorrhage in patients with cirrhosis. N Engl J Med 1983; 309:1539-42.
27. Lebrec D, Poynard T, Bernuau I, et al. A randomized controlled study of propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a final report. Hepatology 1984; 4:355-8.
28. Villeneuve JP, Pomier-Layrargues G, Infante-Rivard C, et'al. Propranolol for the prevention of recurrent variceal hemorrhage: a controlled trial. Hepatology 1986; 6:1239-
29. Bernard B, Lebrec D, Mathurin P, Opolon P, Poynard T. Beta-adrenergic antagonists in the prevention of gastrointestinal rebleeding in patients with cirrhosis: a meta-analysis. Hepatology 1997: 25:63-70.
30. Gournay J, Masliah C. Martin T, Perrin D, Galmiche JP. Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of variceal rebleeding. Hepatology 2000; 31 :1239-45.
31. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding: a meta-analysis. Ann Intern Mod 1995; 123:280-7.
32. Heresbach D, Jacquclinet C, Nouel O, et al. Sclerotherapy versus ligation in hemorrhage caused by rupture of esophageal varices. Direct meta-analysis of randomized trials. Gastroenterol Clin Biol. 1995 Nov;9(11):914-20.
33. Stiegmann CV, Goff JS, Michaletz-Onody PA, et al. Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices. N Engl J Mod 1992; 326:1527-32.
34. Lo GH, Lai KH, Chieng JS, et al. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology 1995; 22:466-71.
35. Saeed ZA, Stiegmann GV, Ramirez FC, et al. Endoscopic variceal ligation is superior to combined ligation and sclerotherapy for esophageal varices: a multicenter prospective randomized trial. Hepatology 1997; 25:71-4.
36. Laine L, Stein C, Sharma V. Randomized comparison of ligation versus ligation plus sclerotherapy in patients with bleeding esophageal varices. Gastroenterology 1996; 110:529-33.
37. D. Patch, C.A. Sahir, J. Goulis, G. Gerunda, L. Greenslade. C. Merkel et al., A randomized controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis, Gastroenterology 123 (2002) 1013-1019
38. Agrawal SR, Gupta R, Murthy NS, Sarin S. Comparable efficacy of propranolol plus isosorbide mononitrate and endoscopic variceal ligation in prevention of variceal rebleed. J Hepatol. 2002; 36[suppl]:631A.
39. G.H. Lo, W.C. Chen, M.H. Chen, P.I. Hsu, C.K. Lin, W.L. Tsai et al., Banding ligation versus nadolol and isosorbide mononitrate for the prevention of esophageal variceal rebleeding, Gastroenterology 123 (2002) 728-734
40. Villanueva C, Minana J, Orlil J, et al. Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med 2001; 345:647-55
41. Lo GH, Lai KH, Cheng JS, et al. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial. Hepatology 2000; 32:461-5.
42. Rossle M, Piotraschke J. Transjugular intrahepatic portosystemic shunt and hepalicencephalopathy. Dig Dis 1996; 14:Suppl 1:12-9.
43. Sanyal AJ. Freedman AM, Shiftman ML, Purdum PP III, Luketic VA. Cheatham
AK. Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. Hepatology 1994; 20:46-55.
44. Chalasani N, Clark WS, Martin LG, et al. Determinants of mortality in patients with advanced cirrhosis after transjugular intrahepatic portosystemic shunting. Gastroenterology 2000; 118:138-44.
45. Jabbour N, Zajko AB, Orons PD, et al. Transjugular intrahepatic portosystemic shunt in patients with end-stage liver disease: results in 85 patients. Liver Transpl Surg 1996; 2:139-47
46. Jalan R, Elton RA, Redhead DN, Finlayson ND, Hayes PC. Analysis of prognostic variables in the prediction of mortality, shunt failure, variceal rebleeding and encephalopathy following the transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage. J Hepatol 1995;23:123-8.
47. A. Escorsell, R. Banares, J.C. Garcia-Pagan, R. Gilabert, E. Moitinho, B.Piqueras et al., TIPS versus drug therapy in preventing variceal rebleeding in advanced cirrhosis: a randomized controlled trial, Hepatology 35 (2002)385-392
48. Rosch I, Keller FS. Transjugular intrahepatic portosystemic shunt; present status, comparison with endoscopic therapy and shunt surgery, and future prospectives. World J Surg. 2001 Mar;25(3):337-45.
49. Eccles M, Clapp Z, Grimshaw J, et al. North Of England evidence based guidelines development project : methods of guideline development. BMJ 1996; 312:760-2.
50. Grimshaw J, Eccles M, Russel I, et al. Developing clinically valid practice guidelines. J Evaluation Clin Pract 1995; 1:37-48.

return to main page