Acute Gastrointestinal Bleeding: Part II.

D. COLLINS, L. I. G. WORTHLEY
Department of Critical Care Medicine, Flinders Medical Centre, Adelaide, SOUTH AUSTRALIA

ABSTRACT Objective: To review the management of acute gastrointestinal bleeding in the critically ill patient in a two part presentation. Data sources: Articles and a review of studies reported from 1991 to 2001 and identified through a MEDLINE search of the English language literature on acute gastrointestinal bleeding. Summary of review: Oesophageal varices are a common source of upper gastrointestinal bleeding in patients who have portal hypertension. Management requires resuscitation and treatment of associated coagulation disturbances along with intravenous octreotide (50 g followed by 50 g/hr for 48 hr) before endoscopy is performed. Octreotide is more effective than vasopressin in controlling acute variceal haemmorhage and has fewer side effects compared with glypressin. To provide haemostasis, endoscopic variceal scerosis has largely been replaced by variceal ligation using an overtube and small elastic o rings to band the bleeding variceal channels. If bleeding continues then balloon tamponade and intravenous fibrinolytic inhibitors (e.g. tranexamic acid 3 - 6 g i.v. daily) are used for 24 hr before endoscopy (with variceal ligation) is repeated. If the variceal bleeding is resistant to repeated banding, portal decompression using transjugular intrahepatic portosystemic shunt or surgical shunt should be considered. While beta adrenergic blockers (e.g. propranalol) are indicated to reduce the incidence of rebleeding, they are contraindicated in a patient with actively bleeding oesophageal varices. Conclusions: Acute oesophageal variceal bleeding can often be managed successfully using octreotide and variceal ligation. If bleeding continues then transjugular intrahepatic portosystemic shunt or surgical shunt should be considered. (Critical Care and Resuscitation 2001; 3: 117-124) Key Words: Acute gastrointestinal bleeding, oesophageal and gastric varices, somatostatin analogs and derivatives, transjugular intrahepatic portosystemic shunt, liver cirrhosis

BLEEDING OESOPHAGEAL VARICES The anastomosis between splanchnic and systemic venous systems occur at the gastroesophageal junction (via thin-walled submucosal oesophageal veins channeling blood to the azygous and hemiazygous veins), in the retroperitoneal space between the kidneys and spleen, between the mesenteric and gonadal veins, and around the umbilicus, diaphragm and rectum (Figure 1). Portal venous pressures normally range from 5 to 10 mmHg and portal hypertension is present if the direct portal vein pressure is greater than 12 mmHg.1 In patients who have bleeding oesophageal varices, the portal venous pressures range from 12 to 40 mmHg,2 with the risk of oesophageal variceal bleeding low when the differences

in portal vein and inferior vena cava pressures are less than 12 mmHg.3 In one study, the risk of bleeding from varices was essentially zero if the hepatic venous pressure gradient was reduced to below 12 mmHg.4 Portal hypertension is often classified according to the site of obstruction to portal blood flow. For example, presinusoidal (which may be prehepatic, e.g. portal and splenic vein thrombosis,5 or intrahepatic, e.g. schistosomiasis, myelofibrosis, leukaemic infiltration, sarcoid), sinusoidal (e.g. cirrhosis), and postsinusoidal (e.g. Budd-Chiari syndrome). Sixty percent of patients with cirrhosis develop oesophageal varices, and 66% of these bleed (i.e. 40% of confirmed cirrhotic patients develop variceal haemorrhage6), usually from vessels in

Correspondence to: Dr. D. Collins, Department of Critical Care Medicine, Flinders Medical Centre, Bedford Park, South Australia 5042

117

D. COLLINS, ET AL the lower 5 cm of the oesophagus.7 Portal hypertension may also cause gastric bleeding from portal hypertensive gastropathy (a condition which can cause diffuse gastric mucosal bleeding and may follow sclerotherapy8) or gastric varices.

Critical Care and Resuscitation 2001; 3: 117-124 Resuscitation This involves blood transfusion, correction of coagulation abnormalities (e.g. fresh frozen plasma, platelets) and correction of vitamin deficiencies that may cause coagulation abnormalities (e.g. Vitamin K, folic acid). As variceal haemorrhage is associated with a high incidence of severe bacterial infections (e.g. Gramnegative septicaemia), all patients should have blood cultures taken and given i.v. ciprofloxacin 200 mg 12hourly (or oral norfloxacin 400 mg 12-hourly) for 7 days.18 Endoscopic variceal sclerosis (sclerotherapy) Sclerotherapy has often been used for both acute oesophageal variceal haemorrhage (once resuscitation is complete and temporary haemostasis has been achieved, which may require intravenous octreotide, vapreotide, vasopressin, or balloon tamponade19) and rebleeding prevention.20,21 It has a greater success rate than balloon tamponade in controlling acute oesophageal variceal haemorrhage (e.g. 90% for sclerotherapy, compared with 40 - 80% for balloon tamponade) and the 6-month survival rate is better (e.g. 84% for sclerotherapy compared with 45% for balloon tamponade).6 It also has a lower incidence of portal-systemic encephalopathy when compared with transjugular intrahepatic portosystemic shunts.22 The combination of sclerotherapy and octreotide (25 g/hr for 5 days) is more effective than sclerotherapy alone in controlling acute variceal bleeding.23 Sclerotherapy is performed during endoscopy, using a sclerosant (e.g. alcohol, ethanolamine) injected into the varix (if the varix is actively bleeding), or adjacent submucosa (if the varix is not actively bleeding). This may be repeated at weekly intervals, causing intraluminal thrombosis, fibrous organisation and progressive variceal obliteration.24 While gastric varices decrease in the majority of patients after eradication of oesophageal varices,20 sclerosis is ineffective in controlling acute bleeding from gastric varices or from portal hypertensive gastropathy.25 Prophylactic sclerotherapy in patients who have oesophageal varices which have not bled is of no benefit,9,20,21,26 and in one report was associated with an increase in mortality.27 While another study reported prophylactic endoscopic ligation of oesophageal varices that had never bled was more effective than propranalol in the prevention of variceal bleeding,28 propranalol is still preferred for primary prevention of non-bleeding oesophageal varices.29 Complications of sclerotherapy include dysphagia, retrosternal pain, fever, rebleeding, bacteraemia, mediastinitis, pleural effusions, empyema, paraoesophageal

Figure 1. Sites of portosystemic circulation in cirrhosis of the liver

Treatment While asymptomatic oesophageal varices do not require treatment,7,9 variceal bleeding requires therapy to control the acute bleeding episode as well as to reduce the incidence of rebleeding, as rebleeding occurs in 70% or more of cirrhotics who have survived their first variceal haemorrhage.10 Endoscopy should be performed in all patients who have upper gastrointestinal bleeding and oesophageal varices, as a nonvariceal source of bleeding (e.g. gastric erosions, or chronic ulceration) may be found in up to 50% of patients.11 The percentage of patients in whom bleeding is controlled, and the mortality associated with the various treatments for acute variceal haemorrhage are listed in Table 1.7,10,12-17 118

Critical Care and Resuscitation 2001; 3: 117-124 Table 1. Treatment

D. COLLINS, ET AL

Treatment of acute variceal bleeding in alcoholic cirrhosis % control % rebleed Hospital mortality (%) of acute haemorrhage Child's A C 70 30 40 50 40-60 10 10 10 3 5 7 15 3 15 95 80 50 60 60 80 50

No therapy 40 Sclerotherapy 95 Somatostatin 250 g/h 60 Vasopressin 0.4 u/min 50 Balloon tamponade 40-80 Percutaneous portacaval shunt 95 Emergency portacaval shunt 90

abscess, aspiration, pneumonia, ARDS, portal vein thrombosis, spinal cord paralysis, oesophageal ulceration, oesophageal perforation, and oesophageal strictures.20,30 Endoscopic variceal ligation Endoscopic variceal ligation, by the application of small elastic o rings over variceal channels, is a technique which has recently been introduced to manage oesophageal variceal bleeding. The method appears to have results that are at least equal to sclerotherapy, with lower rates of rebleeding, lower mortality and fewer serious complications.31-33 However, the major disadvantage of variceal ligation is the need to withdraw the endoscope and load bands individually. This requires the passage of an over-tube which is uncomfortable and may traumatise the oesophagus,34 although newer devices have been developed which allow up to six-band ligations without the need for reloading or an overtube.35 A recent meta-analysis of studies comparing endoscopic ligation with sclerotherapy for treatment of oesophageal variceal bleeding concluded that ligation should be considered the endoscopic treatment of choice for patients with oesophageal variceal bleeding.36 Also the combination of endoscopic ligation and octreotide (50 g bolus followed by 50 g/hr for 5 days) is more effective than endoscopic ligation alone in controlling acute variceal bleeding.37 Vasopressin Intravenous vasopressin at 20 units (U) in 200 mL of 5% dextrose in 20 min followed by 0.2 - 0.8 U/min for 24 hr, will often reduce portal pressure and allow temporary control of variceal haemorrhage in 50% of patients.6 However, rebleeding is frequent. As intraarterial vasopressin at 0.05-0.4 U/min is no more effective than intravenous vasopressin,38,39 and as it is associated with a greater number of complications,2 the intravenous route is usually preferred. The side-effects of vasopressin include diarrhoea, colic, hypertension,

bowel ischaemia and coronary ischaemia. Bowel and coronary ischaemia and hypertension may be reduced by simultaneously infusing glyceryl trinitrate at 40 - 400 g/min (or one tablet sublingually every hour for 6 hr7,40); however, it does not improve the efficacy of vasopressin.12 In one study, 2 mg intravenously, 6hourly of the synthetic analog Glypressin (which is slowly broken down to lysine-vasopressin in the circulation), had a higher success rate in controlling acute variceal haemorrhage when compared to vasopressin at 0.4 U/min.41 However, the prolonged vasomotor side-effects of glypressin may be disadvantageous when compared with vasopressin.12 Somatostatin and somatostatin analogues (octreotide, lanreotide and vapreotide) Somatostatin and analogues (e.g. octreotide, vapreotide) reduce portal pressure, are more effective in controlling acute variceal haemorrhage than vasopressin and are associated with fewer adverse effects.42,43 Octreotide (50 g intravenously followed by 25-50 g/hr for 48 hr, i.e. 500 g of octreotide in 50 mL of 5% dextrose at 2.5 - 5 mL/hr) has been found to be equally as effective as emergency sclerotherapy44 and balloon tamponade in management of variceal bleed-ing.45 In one randomised controlled in patients with cirrhosis and variceal bleeding, vapreotide (50 g i.v. bolus followed by 50 g per hour for five days) begun before endoscopic therapy (e.g. sclerotherapy or band ligation) was more effective than endoscopic therapy alone.46 However, in another randomised, controlled trial and a meta-analysis of two trials failed to show a clinical benefit of somatostatin in the emergency treatment of bleeding oesophageal varices.47 Fibrinolytic inhibitors Tranexamic acid (1 g 8-hourly oral or i.v) has been used to successfully reduce the bleeding of portal gastropathy and gastric antral vascular ectasia in cirrhotic patients.48 119

D. COLLINS, ET AL Beta-adrenergic blockers Beta-adrenergic blockers reduce portal venous pressure by two mechanisms: by decreasing cardiac output (by blocking 1 receptors) and by producing splanchnic vasoconstriction (through 2 receptor blockade and unopposed -adrenergic activity on splanchnic vessels). Predictably, nonselective beta-adrenergic blockers (e.g. propranalol, nadolol, timolol) are more effective than selective beta-adrenergic blockers in reducing portal venous pressure. Propranolol is contraindicated in a patient with actively bleeding oesophageal varices. However, it reduces the incidence of variceal rebleeding (by decreasing the splanchnic blood flow and therefore portal pressure) and should be used after the first bleed at 40 - 360 mg/day (mean 160 mg/day) to reduce the resting pulse rate by 25%,49-51 in the well compensated cirrhotic patient (e.g. Childs class A), who has no contraindications for propranolol use.1,6 While some studies comparing chronic sclerotherapy with beta-blockers have shown that the two treatments are equivalent with respect to rebleeding and mortality, and that combination therapy with sclerotherapy and beta-blockers showed no advantage,52 a recent study comparing sclerotherapy with a combination of a beta-blocker and a vasodilator (nadolol 80 mg daily initially and adjusted to decrease the heart rate by 25% or no less than 55 per minute, and isosorbide-5mononitrate added after the nadolol had been adjusted and increased up to 40 mg 12-hourly, unless side effects appeared), demonstrated that the combination drug therapy significantly decreased the risk of rebleeding with a trend towards improved survival.53 Currently, (following endoscopic band ligation) a non-selective beta-blocker (e.g. propranalol or nadolol) with, or without, isosorbide dinitrate, are advocated as the treatment of choice in the prevention of rebleeding.54 Other drugs Pentagastrin, and metoclopramide constrict the lower oesophageal sphincter and have been reported to control acute variceal bleeding in more patients than in a control group.7 Isosorbide-5-mononitrate has been suggested as an alternative to beta-blockers for variceal haemorrhage prophylaxis, particularly in patients intolerant to betablockade.34 Balloon tamponade Balloon tamponade should be reserved for acute variceal bleeding uncontrolled by sclerotherapy, octreotide, or vasopressin.13 The incidence of rebleeding after removing the balloon is about 50%.13 The LintonNachlas tube has a single lumen which is inflated in the gastric fundus and compresses the varices at the gastric 120

Critical Care and Resuscitation 2001; 3: 117-124 side of the oesophagogastric junction (Figure 2). The Sengstaken-Blakemore tube has an oesophageal balloon as well as a gastric balloon, for both oesophageal and gastric compression (Figure 2). The Minnesota tube has four lumens; two are used to inflate the oesophageal and gastric balloons; the remaining lumens allow for gastric and oesophageal aspiration. The Minnesota tube is often the preferred tube for balloon tamponade management. Technique. Before inserting the tube, the balloons are checked for leaks. The gastric balloon is inflated progressively by 100 mL amounts of air, and the press-

Figure 2. A diagragmatic representation of the SengstakenBlakemore tube (A) in position and the Linton-Nichlas tube (B) in position (Modified from Burcharth F and Malmstrom J. Surg Gynecol Obstet 1976;142:529-531).

ure is recorded with each 100 mL inserted (enabling one to monitor the gastric balloon inflation pressure on insertion, to check that the balloon is not in the oesophagus). The tube is placed through the nose (as nasal insertion is tolerated better and is associated with less aspiration than oral insertion). If oral insertion of the tube is required, the patient requires endotracheal tube intubation with a cuffed tube (and therefore anaesthesia) to protect the airway. The tip of the tube is inserted up to the 60 cm mark before the gastric balloon is inflated. The gastric balloon is filled with 200-500 mL of air and gently drawn up to the fundus of the stomach. The tube is then firmly secured to the face by taping, or by traction of no greater than 1 kg (usually 500 - 1000 mL of saline is used as gravity traction). It is seldom necessary to inflate the oesophageal balloon if the gastric balloon is correctly placed.55 The stomach should be continuously aspirated to assess bleeding control. If bleeding continues, the oesophageal balloon is inflated with air to a pressure of 40 mmHg. The positions of the balloons are checked radiologically. Pharyngeal aspiration should be continuous when the oesophageal balloon is inflated. If bleeding is controll-ed, the oesophageal balloon is left inflated for 24 hr only (deflating the oesophageal balloon for 30-60 min every

Critical Care and Resuscitation 2001; 3: 117-124 8 hr). The gastric-balloon tamponade can be maintained continuously for 48-72 hr, after which it is deflated and bleeding assessed before it is removed. If bleeding continues, the patient should be considered for a surgical procedure (e.g. sclerotherapy, portosystemic shunt or oesophageal transection) or a transjugular intrahepatic portosystemic shunt. The complications associated with balloon tamponade include, aspiration pneumonia, upper airway obstruction, oesophageal rupt-ure and hiccups. Surgical management Surgical management may be divided into those methods which involve decompression of the splanchnic circulation (e.g. central or selective porto-systemic shunts), a direct attack on the varices (e.g. endoscopic or transhepatic sclerosis, transection by stapling, transoesophageal ligation, devascularisation) or replacement of the diseased liver (i.e. hepatic transplantation). Rebleeding after a variceal decompressive shunt usually indicates a technical failure (duplex sonography is often used to confirm shunt occlusion). Child developed a classification to assess the hepatic reserve to tolerate a major operation and consequence of a diminished portal flow to the liver.56 The risk of operation is good with class A, moderate with class B and poor with class C. Childs classification has subsequently been modified by including prolongation of prothrombin time, excluding the excellent, good and poor nutritional classification and classifying a patient with a score. A score of 5 or 6 is class A, 7, 8 or 9 is class B, and 10 to 15 is class C (i.e. Child-Pugh class. Table 2).57 Central portosystemic (i.e portacaval) shunts. Surgical. Four prospective randomised trials comparing central portosystemic (i.e. portacaval) shunting with medical therapy for patients who have cirrhosis and confirmed variceal haemorrhage concluded that shunting prevented rebleeding. However, survival rates were not Table 2.

D. COLLINS, ET AL significantly different. Central shunting seem-ed to alter the mode of death from exsanguination to hepatic failure and encephalopathy.58-61 Percutaneous. A transjugular intrahepatic portosystemic shunt (TIPS), using a balloon-expandable stent has made the decompression of portal vein hypertension extremely simple (by reducing the difference between portal venous and inferior vena cava values to 12 mmHg), reducing the patient's postprocedure stay to a few days (Figure 3). The procedure does not preclude liver transplantation at a later date (although difficulty in removing the stent from the inferior vena cava and portal vein thrombosis have been reported62) and in skilled hands has become treatment of choice (irrespective of the patients Child classification) in reducing portal venous pressure in the management of difficult variceal bleeding (i.e. continued oesophageal bleeding despite two sclerotherapy sessions or bleeding caused by gastric varices or portal hypertensive gastropathy).17,25,63,64 During the insertion of the shunt and in the presence of active bleeding, shunt venography can be performed and thrombogenic emboli may be inserted directly into the bleeding varix. TIPS has also been used to treat refractory ascites.65 The shunt is often reviewed on a three month basis using duplex sonography, and the stent is redilated if there is greater than 50% reduction in shunt flow.25 While TIPS is more effective than endoscopic treatment (i.e. sclerotherapy and/or banding ligation) plus propranalol in prevention of variceal rebleeding, it is associa ted with an increased incidence of hepatic encephalopathy (particularly if the portal pressure is reduced excessively) and the mortality at 12 months is no different.66 As TIPS creates a side to side portosystemic shunt, hepatic encephalopathy and deterioration in liver function occur in up to 25% of cases,52 and shunt malfunction (e.g. stenosis) occurs in more than 50% after 6

Child-Pugh classification of hepatic functional reserve points scored for abnormality 1 2 3 None None < 35 > 35 < 1.3 5-15% 1 and 2 Easily controlled 35 - 50 30 - 35 1.3 - 1.5 15-30% 3 and 4 Poorly controlled > 50 < 30 > 1.5 30-60%

Encephalopathy (grade) Ascites Total serum bilirubin (mol/L) Serum albumin (g/L) INR Post operative mortality

121

D. COLLINS, ET AL months.66 Other problems related to the procedure include perforation of the hepatic capsule with intraabdominal haemorrhage and visceral perforation, infection, arrhythmias, thrombosis, misplaced or migrating stents, renal failure and haemolytic anaemia.67

Critical Care and Resuscitation 2001; 3: 117-124 However, while the procedure is associated with acceptable mortality, is efficacious in controlling haemorrhage and has minimal propensity for precipitating hepatic encephalopathy; most prospective randomised trials to date have shown no difference in mortality when compared with the central shunt procedures.70,71 Some trials have even shown no difference in encephalopathy rate when compared with central portosystemic shunt procedures.72
Received: 20 April 2001 Accepted: 22 May 2001

REFERENCES
1. 2. 3. 4. Bass NM. Preventing hemorrhage from esophageal varices. N Engl J Med 1987;317:893-895. Collini FJ, Brener B. Portal hypertension. Surg Gynecol Obstet 1990;170:177-192. Garcia-Tsao G, Groszmann RJ, Fisher RL, et al. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985;5:419-424. 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;99:1401-1407. Cohen J, Edelman RR, Chopra S. Portal vein thrombosis: a review. Am J Med 1992;92:173-182. Cello JP, Crass RA, Grendell JH, Trunkey DD. Management of the patient with haemorrhaging esophageal varices. JAMA 1986;256:1480-1484. Terblanche J, Burroughs AK, Hobbs KEF. Controversies in the management of bleeding esophageal varices (First of two parts). N Engl J Med 1989;320:1393-1398. D'Amico G, Montalbano L, Traina M, et al. Natural history of congestive gastropathy in cirrhosis. Gastroenterology 1990;99:1558-1564. Terblanche J, Burroughs AK, Hobbs KEF. Controversies in the management of bleeding esophageal varices (Second of two parts). N Engl J Med 1989;320:1469-1475. Burroughs AK. The management of bleeding due to portal hypertension. Part 2. Prevention of variceal rebleeding and prevention of the first bleeding episode in patients with portal hypertension. Q J Med 1988;68:507-516. Stanley AJ, Hayes PC. Portal hypertension and variceal haemorrhage. Lancet 1997;350:1235-1239. Burroughs AK. The management of bleeding due to portal hypertension. Part 1. The management of acute bleeding episodes. Q J Med 1988;67:447-458. Joffe SN. Non-operative management of variceal bleeding. Br J Surg 1984;71:85-91. Bosch J. Effect of pharmacological agents on portal hypertension: a haemodynamic appraisal. Clin Gastroenterol 1985;14:169-184. Bernuau J, Rueff B. Treatment of acute variceal bleeding. Clin Gastroenterol 1985;14:185-207.

5. 6. 7.

Figure 3 Transjugular intrahepatic portosystemic shunt. Top left: a needle is advanced from the hepatic to portal vein via a transjugular approach. Top right: a guidewire is advanced through the needle into the portal vein. Centre left: an angioplasty balloon is advanced over the guidewire and expanded across the hepatic parenchymal tract. Centre right: a stent mounted on the angioplasty balloon, is expanded to bridge the hepatic and portal veins. Lower final: appearance of the intrahepatic shunt with the stent in place (Reproduced, with permission, from Zemel G, et al. JAMA 1991;266:390-393).

8. 9.

Selective portosystemic (i.e. distal splenorenal) shunts. The creation of a distal splenorenal shunt (i.e. Warren shunt), selectively decompresses varices by separating the splanchnic circulation into two components, the portomesenteric and the gastrosplenic. The latter is decompressed into the systemic venous circulation via the left renal vein, which reduces pressure in the oesophageal varices and prevents haemorrhage. Because the portomesenteric circulation is separate and not decompressed, portal perfusion and thus hepatic function is preserved. The incidence of postshunt encephalopathy in some studies has been greatly reduced.68,69 This procedure does not preclude liver transplantation at a later date. The procedure is technically more difficult than the standard portacaval shunt. 122

10.

11. 12. 13. 14. 15.

Critical Care and Resuscitation 2001; 3: 117-124

16. 17. 18. Westaby D. The management of active variceal bleeding Intens Care Med 1988;14:100-105. Zemel G, Katzen BT, Becker GJ, Benenati JF, Sallee S. Percutaneous transjugular portosystemic shunt. JAMA 1991;266:390-393. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology 2001;120:726-748. Sherlock S. Esophageal varices. Am J Surg 1990;160:913. Sarin SK. Endoscopic sclerotherapy for esophagogastric varices. Aust NZ J Med 1989;19:162-171. Bullimore DW, Foster P. Prophylactic sclerotherapy for varices. Br Med J 1988;297:370-371. Sanyal AJ, Freedman AM, Shiffman 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. Besson I, Ingrand P, Person B, et al. Sclerotherapy with or without octreotide for acute variceal bleeding. N Engl J Med 1995;333:555-560. Westaby D, MacDougal BRD, Williams R. Improved survival following injection sclerotherapy for oesophageal varices: final analysis of controlled trial. Hepatology 1985;5:627-631. McCaughan GW. Transvenous intrahepatic portosystemic shubnt (TIPSS): a new treatment for portal hypertension. Aust NZ J Med 1994;24:133-135. Editorial. Prophylactic sclerotherapy of oesophageal varices: is it justified? Lancet 1988;i:1369-1370. The Veterans Affairs Cooperative Variceal Sclerotherapy Group. Prophylactic sclerotherapy for esophageal varices in men with alcoholic liver disease. A randomized, single-blind, multicenter trial. N Engl J Med 1991;324:1779-1784. Sarin SK, Lamba GS, Kumar M, Misra A, Murthy NS. Comparison of endoscopic ligation and propranalol for the primary prevention of variceal bleeding. N Engl J Med 1999;340:988-993. Burroughs AK, Patch D. Primary prevention of bleeding from oesophageal varices. N Engl J Med 1999;340:1033-1034. Health and Public Polocy Committee American College of Physicians. Endoscopic sclerotherapy for esophageal varices. Ann Intern Med 1984;100:608-610. 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;326:1527-1532. 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. Sivak MV Jr, Catalano MF. Endoscopic ligation of esophageal varices. Ann Intern Med 1993;119:87-88. Hayes PC. Portal hypertension revisited. Q J Med 1995;88:751-754. 35. 36.

D. COLLINS, ET AL
Saeed ZA. Endoscopic esophagogastric variceal ligation with a six-shot multiple ligation device. Am J Gastroenterol 1995;90:1570. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A meta-analysis. Ann Intern Med 1995;123:280-287. Sung JJY, Chung CSC, Yung MY, et al. Prospective randomised study of effect of octreotide on rebleeding from oesophageal varices after endoscopic ligation. Lancet 1995;346;1666-1669. Chojkier M, Groszmann RJ, Atterbury CE, et al. A controlled comparison of continuous intraarterial and intravenous infusions of vasopressin in hemorrhage from esophageal varices. Gastroenterology 1979;77:540546. Conn HO, Ramsby GR, Storer EH, et al. Intra-arterial vasopressin in the treatment of upper gastrointestinal hemorrhage: a prospective controlled clinical trial Gastroenterology 1975;68:211-221. Gimson AE, Westaby D, Hegarty J, et al. A randomized trial of vasopressin and vasopressin plus nitroglycerin in the control of acute variceal haemorrhage. Hepatology 1986;6:410-413. Freedman JG, Cobden F, Lishman AH, Record CO. Controlled trial of terlipressin ('glypressin') versus vasopressin in the early treatment of oesophageal varices. Lancet 1982;ii:66-67. Jenkins SA, Baxter JN, Corbett W, Devitt P, Ware J, Shields R. A prospective randomised controlled clinical trial comparing somatostatin and vasopressin in controlling acute variceal haemorrhage. Br Med J 1985;290:275-278. Hwang JJ, Liu HC, Chang CF, et al. A randomised controlled trial comparing octreotide and vasopressin in the control of acute variceal bleeding. J Hepatology 1992;16:320-325. Sung JJY, Chung SCS, Lai C-W, et al. Octreotide infusion or emergency sclerotherapy for variceal haemorrhage. Lancet 1993;342:637-641. McKee R. A study of octreotide in oesophageal varices. Digestion 1990;45 (suppl):60-65. Cales P, Masliah C, Bernard B, et al. Early Administration of Vapreotide for Variceal Bleeding in Patients with Cirrhosis. N Engl J Med. 2001;344:23-28. Gtzsche PC, Gjrup I, Bonnn H, et al. Somatostatin v placebo in bleeding oesophageal varices: randomised trial and meta-analysis. Br Med J 1994;310:1495-1498. McCormick PA, Ooi H, Crosbie O. Tranexamic acid for severe bleeding gastric antral vascular ectasia in cirrhosis. Gut 1998;42:750-752. LeBrec D, Poynord T, Bernau J, et al. A randomized controlled study of propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis. A final report. Hepatology 1984;4:355-358. Kiire CF. Controlled trial of propranolol to prevent recurrent variceal bleeding in patients with non-cirrhotic portal fibrosis. Br Med J 1989;298:1363-1365. Pascal J-P, Cales P, and a Multicenter Study Group. Propranolol in the prevention of first upper

37.

19. 20. 21. 22.

38.

39.

23. 24.

40.

41.

25. 26. 27.

42.

43.

28.

44. 45. 46. 47. 48. 49.

29. 30. 31.

32.

33. 34.

50. 51.

123

D. COLLINS, ET AL
gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 1987;317:856-861. Standford NL, Kerlin P. Current management of oesophageal varices. Aust NZ J Med 1995;25:528-534. Villanueva C, Balanz J, Novella MT, et al. Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal bleeding. N Engl J Med 1996;334:1624-1629. Bosch J. Prevention of variceal rebleeding: endoscopes, drugs, and more. Hepatology 2000;32:660-662. Vlavianos P, Gimson AES, Westaby D, Williams R. Balloon tamponade in variceal bleeding: use and misuse. Br Med J 1989;298:1158. Child CG. The liver and portal hypertension. W. B. Saunders Co. Philadelphia 1974. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-649. Jackson FC, Perrin EB, Felix WR, Smith AG. A clinical investigation of the portocaval shunt. V. Survival analysis of the therapeutic operation. Ann Surg 1971;174:672-698. Resnick RH, Iber FL, Ishihara AM, Chalmers TC, Zimmerman H. A controlled study of the therapeutic portocaval shunt. Gastroenterology 1974;67:843-857. Reuff B, Prandi D, Degos F, et al. A controlled study of therapeutic portocaval shunt in alcoholic cirrhosis. Lancet 1976;i:655-659. Reynolds TB, Donovan JA, Mikkelsen WP, Redeker AG, Turrill FL, Weiner JM. Results of a 12 year randomized trial of portocaval shunt in patients with alcoholic liver disease and bleeding varices. Gastroenterology 1981;80:1005-1011. 62.

Critical Care and Resuscitation 2001; 3: 117-124

Millis PM, Martin P, Shaked A, Goldstein L, Colquhoun SD, Busutil KW. TIPPS and liver transplantation: technical considerations. Hepatology 1993;18:65A. Rssle M, Haag K, Ochs A, et al. The transjugular intrahepatic portosystemic stent-shunt procedure for variceal bleeding. N Engl J Med 1994;330:165-171. Conn HO. Transjugular Intrahepatic portal-systemic shunts. The state of the art. Hepatology 1993;17:148158. Ochs A, Rssle M, Haag K, et al. The transjugular intrahepatic portosystemic stent-shunt procedure for refractory ascites. N Engl J Med 1995;332:1192-1197. Rssle M, Deibert P, Haag K, et al. Randomised trial of transjugular-intrehepatic-portosystemic shunt versus endoscopy plus propranalol for prevention of variceal rebleeding. Lancet 1997;349:1043-1049. Conn HO. Hemolysis after transjugular intrahepatic portosystemic shunting: the naked stent syndrome. Hepatology 1996;23:177-181. Rikkers LF, Rudman D, Galambos JT, et al. A randomized controlled trial of the distal splenorenal shunt. Ann Surg 1978;188:271-280. Reichle FA, Fahmy WF, Golsorkhi M. Prospective comparative clinical trial with distal splenorenal and mesocaval shunts. Am J Surg 1979;137:13-18. Maillard J-N, Flamant YM, Hay JM, Chandler JG, Selectivity of the distal splenorenal shunt. Surgery 1979;86:663-671. Conn HO, Resnick RH, Grace ND, et al. Distal splenorenal shunts vs. porto-systemic shunt: current status of a controlled trial. Hepatology 1981;1:151-160. Henderson JM. Variceal bleeding: which shunt? Gastroenterology 1986;91:1021-1023.

52. 53.

63. 64. 65. 66.

54. 55. 56. 57. 58.

67. 68. 69. 70. 71. 72.

59. 60. 61.

124