Saudi Journal of Gastroenterology

ARTICLES
Year
: 1995  |  Volume : 1  |  Issue : 1  |  Page : 25--30

Variceal bleeding: Management options


Ibrahim A Al Mofleh, Rashed S Al Rashed, Saleh M Al Amri 
 Department of Medicine, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia

Correspondence Address:
Ibrahim A Al Mofleh
Department of Medicine, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461
Saudi Arabia

Abstract

Portal hypertension with esophageal varices represents an important source of upper gastrointestinal bleeding. Variceal bleeding is associated with high rebleeding and mortality rates. Various treatment modalities are effective in control of bleeding. Endoscopic Sclerotherapy (ES) is the standard method for management of acute variceal bleeding alone or in combination with vasoactive drugs. Alternative methods are considered in case of sclerotherapy failure. Portosystemic shunt operation is complicated by systemic encephalopathy. Therefore, it is replaced by other surgical procedures. These include esophageal stapled transection, splenectomy with devascularization, distal splenorenal shunt (DSRS), DSRS combined with pancreatic disconnection, narrow diameter mesocaval (NDMC) or portocaval (NDPC) shunts and liver transplantation . Recently. transjugular intrahepatic portosystemic stent­shunting (TIPSS) has been introduced in the management of patients with refractory variceal bleeding waiting for liver transplanation.



How to cite this article:
Al Mofleh IA, Al Rashed RS, Al Amri SM. Variceal bleeding: Management options.Saudi J Gastroenterol 1995;1:25-30


How to cite this URL:
Al Mofleh IA, Al Rashed RS, Al Amri SM. Variceal bleeding: Management options. Saudi J Gastroenterol [serial online] 1995 [cited 2019 Oct 14 ];1:25-30
Available from: http://www.saudijgastro.com/text.asp?1995/1/1/25/34063


Full Text

In Saudi Arabia and Jordan, bleeding from esophageal varices complicating portal hyperten­sion is prevalent and accounts for 10-40% of upper gastrointestinal bleeding. [1],[2],[3],[4]

Approximately one third of patients with liver cirrhosis bleed from esophageal varices. [5] The outcome of the initial bleeding is influenced by Child-Pugh's grade, the quantity of blood loss, the presence of ascites, bilirubin and blood urea nitro­gen (BUN) plasma level [6] Bleeding from esophageal varices is associated with 50% mortal­ity rate [7] and a high rebleeding rate, 30 and 70% at six weeks and one year respectively. [8] Rebleed­ing is well correlated with the liver function and is more prevalent in patients with Child grade C. [9]

Various therapeutic options are available for the management of bleeding esophageal varices. [Table 1] Pharmacological agents, balloon tam­ponade, endoscopic sclerotherapy, endoscopic variceal ligation and surgical approaches are used with variable success rates.

 Pharmacological agents



Vasopressin is a drug with a constricting effect on the splanchnic circulation and thus lowering the portal pressure. [10] It controls bleeding in 50% patients, however 45% rebleed. [11],[12] Drug adverse effects are dose related and include ischemia, bradycardia, hypertension and decreased hepatic oxygen consumption. Serious cardiac adverse effect occur in approximately 15% of patients. [13] Vasopressin is administered by continuous intravenous infusion (0.4 u/min). The dose is adjusted according to the hemostatic and adverse effects. It is reduced by 0.1 u/min every 6-12 hours after bleeding cessation. [14] Adverse reactions can be prevented or reduced by the simultaneous use of nitroglycerin. [15],[16],[17]

Terlipressin is a longacting vasopressin analogue with similar action. It has been found to be superior to placebo in regard of hemostasis and survival. [11] In combination with nitroglycerin, terlipressin was found to be as effective as balloon tamponade in bleeding control. [18]

Somatostatin induces vasoconstriction of the splanchnic arterioles with a reduction/of the portal flow and the azygos venous blood flow. [19],[20] Somatostatin, in contrast to vasopressin, does not cause systemic vasoconstriction, [20],[21],[22],[23] however, it is expensive with equivocal hemostatic effect. It has been compared with placebo with controver­sial results. [21],[22]

Octreotide, a somatostatin analogue, has signif­icant and prolonged reduction of the portal and hepatic venous circulation in experimental ani­mals. [24] In cirrhotic patients with portal hyperten­sion, octreotide is similar to somatostatin in reduction of the wedged hepatic vein pressure probably due to its constricting effect on the splan­chnic orterioles. [25] It also significantly reduces the azygos venous blood flow [26] without systemic hemodynamic effects. [27] In their preliminary results Jenkins et al. found octreotide as effective as sclerotherapy in the early control of variceal bleeding. [28] Furthermore, octreotide hemostatic effect was comparable to balloon tamponade. [27]

 Balloon tamponade



Balloon tamponade is a simple method, easily accessable and non expensive device that controls variceal bleeding by mechanical compression in approximately 90% of patients. [29],[30] Although this technique has a temporary effect and is com­plicated by a high rebleeding rate, upto 60% after balloon deflation, it is still indicated in massive variceal bleeding and when therapeutic endos­copic techniques are not available.

 Endoscopic methods



Endoscopic sclerotherapy is a fairly old technique which was firstly reported 1939 by Crafoord and Frenkner using a rigid scope. [30] This method has become popular with the development of fiberscope and the high success rate reported in 1973 by Johnston and Rodgers. [31] Nowadays ES is the mainstay of treating bleeding esophageal varices. [32],[34] The most commonly used slerosing agents are polidocanol, ethanolamine oleate, sodium tetradecyl sulfate and morrhurate with no definite superiority of one or the other agent. [35] Other sclerosing agents include absolute ethanol, 50% dextrose with sodium chloride and 15% sodium chloride. [36]

Hemostasis is achieved in approximately 90% of patients undergoing sclerotherapy. [32] How­ever it is associated with a high rebleeding rate before completion of eradication. Paravariceal, intravariceal and combination of both techniques are used for hemostasis of bleeding varices. [34],[37] The efficacy of the paravariceal injection is unsatisfactory and therefore, uncommonly used. [30] Injection of sclerosing agent is associated with inflammatory reaction and formation of edema that induces a mechanical tamponade. This effect decreases after 3-5 days with possible rebleeding. A second injection performed with this period of time may prevent or reduce early rebleeding. [11] The timing of first sclerotherapy has been investigated by Westaby et al. They found a significant improvement of hemostasis when immediate sclerotherapy was performed, compared to sclerotherapy after 12 hours of vas­opressin and nitroglycerin infusion. [33]

Sclerotherapy is associated with a number of esophageal, respiratory and systemic complica­tions. [Table 2] However the rate of serious com­plications does not exceed 10%. Complications can be reduced by improvement of the technical expertise and the control of the injected quantity of sclerosing agent. [30] Acute variceal hemorrhage is managed successfully with ES in majority of patients.

Alternative measures (Tables) are indicated in the following conditions: a) Failure to control bleeding after two sclerotherapy sessions, [38] b) rebleeding within 48 hours [11] c) two recurrences during the same hospitalization, [11],[39] d) rebleed­ing from gastric varices [11],[39] and e) bleeding from ulcer complicating sclerotherapy or balloon tam­ponade. [39]

Endoscopic variceal ligation (EVL), was intro­duced in 1986 by Stiegmann et al. using small, elastic 0 rings for variceal ligation. [40] Since then several studies have compared EVL with sclerotherapy. Patient treated with EVL have sig­nificantly lower morbidity and mortality. [41] Gim­son et al. found EVL significantly better than sclerotherapy in regard of the obliteration time, number of endoscopic sessions and rebleeding rate. Both techniques has a similar effect on hemostasis and obliteration. Although EVL is proven to be safe, [41],[42] some complications were reported recently in form of bleeding or perfora­tion related to the use of overtube [43],[44],[45] or to the ulcer formation with massive bleeding or stric­ture. [46]

 Tissue Adhesives



Liquid tissue adhesives were also used for hemostasis with a decline of the rebleeding rate compared to polidocanol, 12.2 and 30.5%, respectively. [37]

 Transjugular intrahepatic portosystemic stent­shunting (TIPSS)



This method was described in 1969 in experi­mental animal by Rosch et al. [47] Colapinto et al. 1982 reported the first application in man. [48] The recent introduction of metallic expandable stents has encouraged further use of this technique in human and was first reported in 1989 by Richter et al. [49] Ring et al. reported 100% hemostasis with a significant reduction of the mean portal pressure with complications in patients with refractory variceal bleeding scheduled for liver transplanta­tion. [50] However, procedure related complica­tions inform of septicemia and fatal intra­peritoneal hemorrhage were reported by other authors. [51] Furthermore, rebleeding due to occlu­sion and encephalopathy may still occur in up to 15 and 30% respectively. [52],[53]

 Surgical Procedures



Before the ara of sclerotherapy, portosystemic shunt (PSS) was the most frequently used technique to treat acute variceal bleeding. Nowa­days surgical options are considered in case of sclerotherapy failure as defined above. Although rebleeding is reduced by PSS it is considered as a major surgery complicated by portosystemic encephalopathy and associated with a high mor­tality rate. [53]

Distal splenorenal shunt (DSRS) as an elective surgery with a less frequent post- shunt encephalopathy has nowadays replaced PSS. [5],[55],[57]

Another effective and simple method for treat­ment of acute variceal bleeding is the esophageal staple transection which controls bleeding in 100% of patients and does not interfere with the hepatic perfusion. [11] The drawback of this proce­dure is the revascularization and rebleeding. [5]

Devascularization and Splenectomy (Hassab) with or without esophageal transection is an effec­tive method in managing variceal bleeding. [58]

Newer surgical shunts preserve the portal per­fusion and therefore, in contrast to PSS have no influence on the liver hemodynamics and func­tion. These techniques includes a combination of DSRS with a total splenopancreatic disconnec­tion, narrow diameter mesocaval (NDMC) or portocaval (NDPC) shunts using a 12 mm ring enforced olytetrafluorethylene prosthesis. [39],[59]

The 5 years survival is better in patients treated surgically by shunt compared to those treated with sclerotherapy. [39]

Liver transplantation is considered as the only definitive treatment for cirrhosis in patients with variceal bleeding. [5],[60] Therefore, the initial techniques, used to control acute variceal bleed­ing should not make a future transplantation dif­ficult. Sclerotherapy, EVL and TIPSS are the methods of choice in transplant candidates. Fur­thermore, mesocaval and mesorenal shunts, which can be easily ligated during transplantation are also recommended. [60]

 Prophylaxis



Only one third of cirrhotic patients bleed from esophageal varices. When bleeding occurs it is associated with high rebleeding and mortality rates. Therefore various prophylactic measures have been evaluated.

Surgery: despite the fact that PSS is effective in prevention of bleeding it is a major surgery with complications and therefore unjustified for prophylaxis. [61],[62]

Sclerotherapy has been used as a prophylactic measure with controversial results. [5],[63],[64],[65],[66],[67] Meta­ analysis of nine studies revealed a superiority of sclerotherapy compared with control. However due to the heterogeneity of these studies, the result should be cautiously considered and sclerotherapy remain unjustified in patients who have not bled from esophageal varices. [35],[68]

B-adrenergic blockers: Non-selective B - adrenergic blockers effect on initial bleeding prophylaxis has been extensively studied and was found to reduce portal pressure in the majority of patients, [69],[70] however up to 50% of patients might fail to show this response [71] B-adrenergic blockers are found to significantly reduce the rate of bleeding, [72],[73] but their effect on survival is uncertain. [35] The efficacy of B-adrenergic bloc­kers is evaluated clinically by the reduction of heart rate. However, reduction of hepatic vein pressure gradient below 12 mm is considered as the best efficacy index of treatment. [72]

The variable non-responder rate, the non-com­pliance, the long duration, the adverse reactions and the cost of treatment limit the routine use of B-adrenergic blockers for the prophylaxis of bleeding from esophageal varices. However, it may be used in patients with large varices which represents a bleeding risk. [74]

 Conclusions



Several options are available to treat acute vari­ceal bleeding after resuscitating the patients. The selection of treatment modality should consider the simplicity, the efficacy and the safety of the method.

Immediate endoscopy after stabilizing the patients and sclerotherapy or variceal banding ligation is the first option. In case of failure to con­trol bleeding other procedures should be consi­dered according to the patients status. In unfit patients TIPSS, in stable patients a surgical proce­dures not interfering with liver hemodynamic are to be considered. In liver transplantation candi­date ES or EVL and in case of failure TIPSS, mesocaval or mesorenal shunt are recommended.

References

1Toukan AU. Upper gastrointestinal hemorrhage in Jor­dan: An analysis of causes, characteristics and outcome Annals of Saudi Medicine 1991; 11:539-46.
2Al Mofarreh M, Fakunle YM, Al Moagel M. Upper gas­trointestinal bleeding among Saudis: Etiology and pre­valence, The Riyadh Central Hospital experience Annals of Saudi Medicine 1991; 11:547-50.
3Barlas S, Khawaja Fl, Abu Labans, Endoscopic findings in 462 patients with upper gastrointestinal hemorrhage at King Fahad Hospital (1406-1409). Third Saudi Sym­posium on Gastroenterology and Hepatology, Riyadh. Rajab 1409 (Feb 1989) A 87.
4Laajam MA, Al-Mofleh IA, Al-Faleh FZ, et al. Upper gastrointestinal endoscopy in Saudi Arabia: Analysis of 6386 procedures. Quarterly Journal of Medicine, New Series 1988: 66:21-5.
5Terblanche J. Issues in gastrointestinal endoscopy: Oesophageal varices: Inject, band. Medicate or operate Scand J Gastroenterol 1992; 27 Suppl 192:63-6.
6Sherlock S. The portal venous systems and portal hyper­tension In diseases of the liver and biliary system. 8th Ed. Oxford: Blackwell Scientific Publications 1989:151-207.
7Fleig WE, Stange EF. Esophageal varices, Endoscopy 1989; 21:89-96.
8Graham D, Smith JL. The course of patients after vari­ ceal hemorrhage. Gastroenterology 1981; 80:800-9.
9The Italian multicenter project. Project for propranolol in prevention of bleeding, propranolol for prophylaxis of bleeding in cirrhotic patients with large varices: A multi center, randomized clinical trial. Hepatology 1989; 8:6­9.
10Obnishi K, Sato S. Effects of vasopressin on left gastric venous flow in cirrhotic patients with esophageal varices. Am J Gastroenterol; 1990; 85:293-5.
11Soderlund C, Eriksson LS. Medical and surgical treat­ment of acute bleeding from esophageal varices in patients with cirrhosis. Scand J Gastroenterol 1991: 26:897-908.
12Grace ND. Variceal hemorrhage: Pharmacologic approach. In McDermott WV, Bothe A (Eds) Surgery of the liver. Boston, Blackwell scientific publications 1988:303-14.
13Bornman PC, Krige JEJ, Terbianche J. Management of oesophageal varices. Lancet 1994; 343:1079-84.
14Grace ND. Portal Hypertension In Bayless TM (ED) current therapy in gastroenterology and liver diseases - 3 B.C. Decker Inc. Toronto - Philadelphia 1990:441-4.
15Groszman RJ, Kravetz D, Bosth J et al. Nitroglycerin improves the hemodynamic response to vasopressin in portal hypertension. Hepatology 1982: 2:757-62.
16Tsai YT, Lay CS, Lai KH et al. Controlled trial of vasop­ressin plus nitroglycerin VS. Vasopressin alone in the treatment of bleeding esophageal varices. Hepatology 1986; 6:406-9.
17Terblanche J, Burroughs AK, Hobbs KEF. Controver­sies in the management of bleeding esophageal varices N Engl J Med 1989; 320:1393-8.
18Fort E, Sautereau D. Silvain C. et al. A randomized trial of terlipressin plus nitroglycerin VS. balloon tamponade in the control of acute variceal hemorrhage. Hepatology 1990;11:678-81.
19Masta: R, Bosch J, Navasa M, et al. Effect of continuous infusion and bolus injection of somatostatin (SMT) on azygos bloodflow and hepatic and systemic hemodynamics in patients with portal hypertension: comparison with vasopressin. Abstract WP-D2. J Hepatology 1986 3(Suppl.):553.
20Gatta A, Merkel C, Bolognesi M et al. Drugs for the treatment of portal hypertension in cirrhosis: Effects on systemic and splanchnic hemodynamics and on liver function. In Dianizani MU, Gentilini P (Eds) Chronic liver damage. Elsevier Science Publishers 1990:255-72.
21Burroughs AK, McCormick PA. Hughes MD, et al. Randomized, double-hind, placebo-controlled trial of somatostatin for variceal bleeding. Gastroenterology 1990;99:1388-95.
22Valenzuela JE, Shubert T, Fogen MR, et al. A multi­center randomized double-bind trial of somatostatin in management of acute hemorrhage from esophageal vari­ces. Hepatology 1989; 10:958-61.
23Kravetz D, Bosch J, Teres J. et al. Comparison of intra­venous somatostatin and vasopressin infusion in treat­ment of acute variceal hemorrhage. Hepatology 1984; 4:442-6.
24Jenkins SA, Baxter IN. Garbett WA et al. The effects of a somatostatin analogue SMS 201-995 on hepatic hemodynamics in the cirrhotic rats. Br J Surg 1985c; 72:864-7.
25Jenkins SA, Baxter IN. Somatostatin and variceal hemorrhage. Intensive The C1in Monitoring 1989:75-80.
26McComick PA, Dick R, Siringo S et al. Octreotide reduces azygous blood flow in cirrhotic patients with por­tal hypertension. Eur J Gastroenterol Hepatol 1990a; 2:489-92.
27Mckee R. A study of octreotide in oesophageal varices. Digestion 1990; 45(Suppl.):60-5.
28, Jenkins SA, Copeland G. Sutton R, et al. Octreotide (SMS) VS. Sclerotherapy for bleeding varices: Prelimi­nary results, Br J Surg 1992; 79 (Abstract) 1224.
29Chojkier M, Conn HO. Esophageal tamponade in the treatment of bleeding varices. Dig Dis Sci 1980; 25:267­-72.
30Idezuki Y, Sanjo K. Bandai Y, et al. Current strategy for esophageal varices in Japan. The Am J of Sur 1990; 160:98-104.
31Crafoord C. Frenckner T. New surgical treatment of c - (Varicous) veins of the esophagus. Act Otolaryngol 1939; 27:422-9.
32Johnston GW, Rodgers HW. A review of 15 years experience in the use of sclerotherapy in control of acute hemorrhage from esophageal varices. Br J Surg 1973; 60:797-800.
33Westaby D, Hayes PC, Gimson AES, et al. Controlled clinical trial of injection sclerotherapy for active variccal bleeding. Hepatology 1989;9:274.
34Terblanche J. Has sclerotherapy altered the manage­ment of patients with variceal bleeding? Am J Surg 1990; 160:37-42.
35Grace ND. A hepatologist's view of variceal bleeding. Am J Surg 1990; 160:26-31.
36Sarin SK, Kumar A. Sclerosants for variceal sclerotherapy: A critical appraisal. Am J Gastroenterol 1990; 85:641-9.
37Soehendra N, de Herr K, Kemprneers J. et al. Sclerotherapy of esophageal varices: acute arrest of gas­trointestinal hemorrhage or long-term therapy Endos­copy 1983; 15:136-40.
38Bornman PC, Terblanche J, Kahn D, et al. Limitation of multiple injection sclerotherapy sessions for acute vari­ceal bleeding. S Afr Med J 1986: 70:34-6.
39Paquet KJ, Mercado MA. Gad HA, Surgical procedures for bleeding esophagogastric varices when sclerotherapy fails: A prospective study. Am J Surg 1990: 160:43-7.
40Van Stiegmann G, Cambre T, Sun JH. A new endoscopic elastic band ligating device. Gastrointest Endoscopy 1986;32:230-3.
41 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.
42Gimson AES, Ramage KJ, Panos MZ, et al. Ran­domized trial of variceal handing ligation versus injection sclerotherapy for bleeding oesophageal varices. Lancet 1993; 342:391-4.
43Goldschmiedt M, Haber G, Kandel G et al. A safety maneuver for placing overtubes during esophageal vari­ces ligation. Gastrointest Endoscopy 1992; 38:399-400.
44Johnson PA, Campbell DR, Antonson CW, et al. Com­plications associated with endoscopic band ligation of esophageal varices. Gastrointest Endoscopy 1993; 39:181-5.
45Birkelhammer C, Madhav G, Lyon S, et al. "Pinch" injury during overtube placement in upper endoscopy. Gastrointest Endoscopy 1993; 39:186-8.
46Saltzman JR, Arora S. Complications of esophageal vari­ceal band ligation. Gartrointest Endoscopy 1993; 39:185­-6.
47Rosch J, Hanafee WN. Snow H. Transjugular portal ven­ography and radiologic portacaval shunt: An experimen­tal study. Radiology 1969; 92:1112-4.
48Colapinto RF, Stronell RD, Birth SJ, et al. Creation of an intrahepatic portosystemic shunt with a Gruntzig bal­loon catheter. Can Med Assoc J 1982; 126:267-8.
49Richter GM, Palmaz JC, Noldge G, et al. Der transjugu­lar intrahepatische portsystemische stent-shunt (TIPSS). Radiologe 1989:29:406-11.
50Ring EJ, Lake JR, Roberts JP et al. Using transjugular intrahepatic portosystemic shunts to control variceal bleeding before liver transplantation. Ann Int Med 1992; 116:304-8.
51Simpson KJ, Chalmers N, Redhead DN, et al. Trans­jugular intrahepatic portsystemic stent shunting for con­trol of acute and recurrent upper gastrointestinal hemor­rhage related to portal hypertension. Gut 1993:34:968-­73.
52LaBerge JM, Ring EJ, Lake JR, et al. Transjugular intra­hepatic porto-systemic shunts: preliminary results in twenty five patients. J Vase Surg 1992; 16:258-67.
53Sanaval AJ, Freedman AM, Schieffman ML, et al. Por­tosystemic encephalopathy (PSE) following transjugular intrahepatic portosystemic shunt (TIPSS), A controlled study. Hepatology 1992;16:85.
54Rueff B, Maillard JN. Portal-systemic shunts in patients with cirrhosis. Dig 1974; 11:414-27.
55Millikan WJ, Warren WD, Henderson JM et al. The Emorv prospective randomized trial selective versus nonselective shunt to control variceal bleeding Ann Surg 1985; 201:712-22.
56Langer B, Taylor BR, Mackenzie DR, et al. Further report of a prospective randomized trial comparing distal splenorenal shunt with end-to side portocaval shunt. Gastroenterology 1985; 88:424-9.
57da Silva LC, Strauss E, Gayatto LCC et al. Randomized trial for the study of the elective surgical treatment of portal hypertension in Mansonic schistosomiasis, Ann Surg 1986: 204:148-53.
58Hassab MA. Gastroesophageal decongestion and splenectomy in the treatment of esophageal varices in bilharzial cirrhosis. Further studies with a report of 355 operations. Surgery 1967; 61:169-76.
59Henderson JM, Warren WD, Millikan WJ, et al. Distal splenorenal shunt with splenopancreatic disconnection. A 4-year assessment. Ann Surg 1989; 210:332- 41.
60Rikkers LF. Definitive therapy for variceal bleeding: A personal view. Am J Surg 1990: 160:80-5.
61Terblanche J. Burroughs AK, Hobbs KEF. Controver­sies in the management of bleeding esophageal varices. N Engl J Med 1989; 320:1393-8.
62Terblanche J. The surgeon's role in the management of portal hypertension. Ann Surg 1989; 209:381-95.
63Paquet KH. Prophylactic endoscopic sclerosing treat­ment of esophageal wall in varices: A prospective con­trolled randomized trial. Endoscopy 1982: 14:4-5.
64Witzel L, Wolbergs E, Merki H. Prophylactic endoscopic sclerotherapy of esophageal varices. Lancet 1985; 1:773-­6.
65Koch H, Hennig H, Grim H, et al. Prophylactic scleros­ing of esophageal varices: results of a prospective con­trolled trial. Endoscopy 1986; 18:40-3.
66Sauerbruch T, Wotzka R, Kopcke W, et al. Prophylactic sclerotherapy before the first episode of variceal hemor­rhage in patients with cirrhosis. N EngI J Med 1988: 319:8-15.
67Santangelo WC, Dueno MI, Estes BL, et al. Prophylactic sclerotherapy of large esophageal varices. N Engl J Med 1988;318:814-8.
68Scherlock S. Esophageal varices. Am J Surg 1990; 160:9­13.
69Lebrec D. Hillon P, Munoz C, et al. The effect of prop­anol on portal hypertension in patients with cirrhosis: A hemodynamic study Hepatology 1982; 2:523-7.
70Lebrec D, B-Blockers and portal hypertension, hemodynamic effect and prevention of recurrent gas­trointestinal bleeding. Hepato-gastroenterol 1990; 37:556-60.
71Vorobioff J, Picabea E, Villavicencio R, et al. acute and chronic hemodynamic effects of propranolol in unselected cirrhotic patients. Hepatology 1987:7:648-53.
72Pascal JP, Cales P. Multicenter study Group. Prop­ranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 1987: 317:856-61.
73Conn Ho, Grace ND, Bosch J, et al. Propranolol in the prevention of the first hemorrhage from esophagogastric varices: A multicenter, randomized clinical trial. Hepatology 1991; 13:902-12.
74Genecin P, Groszman RJ. Portal hypertension in Schiff L, Schiff ER (Eds). Diseases of the liver. JP Lippincott Company, Philadelphia 1993:935-73.