N G
Joshi and A J Stanley
Department of Gastroenterology, Glasgow Royal Infirmary
Corresponding author: Dr AJ Stanley, c/o GI unit, Ward 8/9, Glasgow Royal
Infirmary, Castle Street, Glasgow G4 0SF Tel: 0141 211 4073 Fax: 0141 211
5131
Email: adrian.stanley@northglasgow.scot.nhs.uk
SMJ 2005 50(1): 5-10
BLEEDING from gastro-oesophageal varices is the most serious and life-threatening complication of cirrhosis and accounts for 10% of all cases of bleeding from the upper GI tract.1 Approximately two third of patients with decompensated cirrhosis and one third of those with compensated cirrhosis have varices at the time of diagnosis of their liver disease. However, only about one third of cirrhotic patients will bleed from their varices which accounts for 80-90% of bleeding episodes in these patients.2,3 Despite the advances in treatment of variceal bleeding, mortality remains high at around 40%, being closely related to the severity of underlying liver disease as assessed by Child’s class,4,5,6 and impairment of renalfunction.7 In addition, approximately 70% of survivors have recurrent bleeding within two years with an associated 30% mortality.8
Pathophysiology
Portal hypertension results from both increased resistance to portal blood flow and increased inflow to the portal vein from the splanchnic circulation: P = Q X R, where P is portal venous pressure, Q is the flow and R is resistance. Increased resistance to portal blood flow has two components – a fixed component, related to distortion of vessels from fibrosis and nodules, and a dynamic component, related to vasoactive substances. There has been a lot of interest in the dynamic component because there is potential for development of vasoactive agents to decrease the resistance to portal blood flow. Various neurohumoral factors have been suggested to have a role in the regulation of intrahepatic blood flow.9,10During liver injury stellate cells become activated and their long cytoplasmic processes surrounding the hepatic sinusoids become contractile increasing intrahepatic resistance.11 Endothelin is a very potent vasoconstrictorpeptide and plasma levels are increased in patients with cirrhosis.12,13 Endothelin can lead to direct constriction ofhepatic sinusoids and may also cause contraction of stellate cells.14 Endothelial-derived vasodilators such as nitric oxideand prostacyclin also appear to have an important role. Current research is focusing on pharmacological interventions affecting these substances.
Risk factors for variceal bleeding
A number of factors may lead to variceal bleeding (Table I).
Table I
|
Risk factors for variceal bleeding |
|
1 Child class |
|
2 continued alcohol use |
|
3 size of varices |
|
4 red spots on varices |
|
5 HVPG>12mmHg |
The most important clinical factor associated with increased risk of a first variceal bleed is poor liver function as measured by child class. Continued alcohol use also increases the risk.2 Endoscopic predictors of bleeding include large varices and endoscopic red wale markings on the variceal wall (which may reflect changes in variceal wall structure and tension).2 Among the physical factors,the main determinant of bleeding is variceal wall tension which depends on transmural pressure, the radius of the vessel and the thickness of the vessel wall.15It has been shown that a threshold value of 12mmHg for the hepatic venous pressure gradient (HVPG) is necessary for bleeding from oesophageal varices although there is no linear relationship between the severity of the gradient and the risk of variceal haemorrhage.16,17 Measurement ofHVPG is an invasive procedure which limits its widespread use, but it can be a useful guide for selection of patients for treatment and to monitor their response to pharmacological therapy.
Acute variceal bleeding
A suggested algorithm for variceal bleeding is given in Figure I. Initial management Acute variceal bleeding is a medical emergency and poses a major therapeutic challenge to clinicians. Similar to any case of gastrointestinal haemorrhage, prompt resuscitation with protection of the airway is crucial. Fluid replacement is preferably done with colloids and red cell concentrate, if necessary. The central venous pressure should be maintained at 0-5 cm H2O as overtransfusion can worsen portal hypertension and risk early rebleeding.18Although no studies have shown definite benefit, it is common practice to correct coagulopathy with FFP, cryoprecipitate or platelets in actively bleeding patients. Patients with altered mental status and those with massive variceal bleeding should be intubated for airway protection to avoid aspiration pneumonia. Acute variceal bleeding predisposes to infection, which is associated with failure to control bleeding and an increased risk of rebleeding.19,20 A meta-analysis showed that antibiotic prophylaxis significantly improved survival following G I haemorrhage in cirrhotic patients.21 The BSG Guidelines recommends prophylactic ciprofloxacin 1g a day for one week in all these patients.22
Pharmacological therapy
Empirical pharmacological therapy with vasopressors is a first line approach where variceal haemorrhage is suspected and there is a delay prior to endoscopic therapy. Drugs can be administered early and do not require special expertise. The first vasoactive drug shown to be of benefit in controlling variceal haemorrhage was vasopressin. However, it is no longer used because of its cardiac and systemic side effects.23 Terlipressin is a synthetic vasopressin analogue with fewer side effects and a longer half life allowing bolus administration. It has been shown to significantly improve bleeding control and survival.24,25 It is as effective asvasopressin, nitroglycerine, somatostatin, endoscopic therapy and balloon tamponade.26,27 Terlipressin is givenas 2mg iv bolus followed by 1-2mg iv 4-6 hourly for up to 72 hours. The Cochrane Database of Systematic Reviews suggests that terlipressin is the vasoactive agent of choice in acute variceal bleeding as this is the only agent that has been shown to reduce mortality.28 It is also licensed for usein acute variceal bleeding.
The role of somatostatin and its synthetic analogue octreotide in the management of variceal haemorrhage have also been extensively studied. These drugs stop variceal haemorrhage in up to 80% of patients and have been shown to be equivalent to vasopressin, terlipressin and endoscopic therapy for the control of acute bleeding.27,29 Several trialshave demonstrated beneficial effects of octreotide on early rebleeding and transfusion requirements when combined with endoscopic sclerotherapy or variceal ligation.30,31However, some studies have suggested desensitization to its effects during continuous infusion.32 In addition, a largerandomized trial comparing octreotide with placebo showed no significant difference between the two groups in terms of reduction in the failure to control bleeding, amount of blood transfused, or mortality at 42 or 90 days.33
Endoscopic therapy
Endoscopic therapy revolutionized the treatment of acute variceal haemorrhage. Early endoscopy confirms the diagnosis and allows therapeutic intervention. Current endoscopic treatment controls variceal bleeding in up to 90% of patients. Endoscopic therapy is often provided together with pharmacological treatment although there are scarce data confirming that this practice improves outcome compared with endoscopic treatment alone. Studies have shown that endoscopic sclerotherapy achieves haemostasis in 80-90% of patients with acute oesophageal variceal haemorrhage.34,35 However, it is associated with important complications including perforation, ulceration, stricture and sepsis due to accompanying bacteraemia. Therefore, endoscopic variceal band ligation (VBL) is now the endoscopic treatment of choice. It has been shown to be at least as good as sclerotherapy in achieving initial haemostasis, but has less complications and requires fewer sessions for variceal obliteration.36,37 One drawback of VBLis the limited visibility during major active variceal bleeding, in which case initial sclerotherapy may be easier.
Balloon tamponade
This is an effective method to temporarily control variceal bleeding when definite therapy from endoscopic means, Transjugular Intrahepatic Portosystemic Shunt (TIPSS) or surgery is awaited. It controls the majority of variceal bleeds when properly applied.38 However, major complications such as aspiration and oesophageal perforation occur in approximately 15% of patients.39 For these reasons, balloon placement should only be undertaken by experienced clinicians after an endoscopy has confirmed variceal bleeding and endotherapy, if available, has failed to control the bleeding.
Transjugular intrahepatic portosystemic shunt (TIPSS)
TIPSS is an interventional radiological procedure which creates an intrahepatic shunt between the portal and hepatic veins to reduce portal pressure. TIPSS has established itself as a salvage procedure for the 10% of patients with refractory variceal bleeding uncontrolled by drugs and endoscopic therapy. The success of TIPSS in controlling bleeding is approximately 90%40,41 and the rebleeding rateis 16 - 30% often due to shunt dysfunction. It has clear advantages over surgery in terms of procedure related complications and can be performed in severely ill patients who would be poor surgical candidates.42 However, despite control of bleeding, the mortality in this subgroup of patients remains high.
Surgery
Surgery has been largely superseded by TIPSS as a salvage procedure. However, it has a role in refractory variceal bleeding where TIPSS has been unsuccessful or is technically not feasible due to anatomical reasons. Surgical options include oesophageal transection or shunt surgery. However, the 30 day mortality associated with emergency surgery for variceal bleeding in patients with advanced liver disease is close to 80%.43 Liver transplantation may be undertaken in patients who bleed whilst on the waiting list for transplantation.
Gastric varices
Gastric varices appear to have a lower risk of bleeding than oesophageal varices, but when they bleed, it is likely to be more severe with a high mortality.44 Gastric varices are larger and often lie deeper in the submucosa compared with oesophageal varices. There are few published data on the role of pharmacotherapy in acute gastric variceal bleeding. They are difficult to treat using standard endoscopic means and have high rebleeding rates.45,46,47 This has been attributed to rapid blood flow making thrombus formation difficult. Therefore, early TIPSS or shunt surgery is often considered for gastric variceal bleeding. However, various new endoscopic sclerosants have now become available with data confirming their efficacy.
TIPSS
TIPSS is effective in controlling 90% of gastric variceal bleeding unresponsive to vasoactive agents, sclerotherapy and/or tamponade.48,49,50 The rebleeding rates are reported to be as low as 13.7%with all the episodes occurring within the first two years50. Early TIPSS in gastric variceal bleeding expertise and availability.
Tissue adhesives
Cyanoacrylate (Histoacryl) injection into physiological medium such as blood causes rapid polymerization and occlusion of the vessel. Most of the data on cyanoacrylate injection are from uncontrolled trials and show it to be 70- 80% effective in controlling acute gastric variceal bleeding. A recent randomized control trial in acutely bleeding gastric varices demonstrated superior haemostasis and rebleeding rate compared with band ligation.51 There was also decreased transfusion requirement and complications with improved survival in the cyanoacrylate group. Rare but serious complications include cerebral embolism, pulmonary thromboembolism, splenic infarct and retrogastric abscess.
Thrombin
Endoscopic injections of human and bovine thrombin have been used effectively in both oesophageal and gastric variceal bleeding. In a recently reported small series of use of human thrombin in acutely bleeding gastric varices, it was shown to be effective in achieving haemostasis with a low rate of rebleeding.52 An advantage of thrombin appears to be reduced mucosal damage or treatment related ulceration than is reported with conventional sclerosants and tissue adhesives. However, data are limited and there is much more published evidence with histoacryl. A prospective study comparing TIPSS with histoacryl or thrombin would be helpful.
Balloon- occluded r retrograde transvenous obliteration (BRTO) of gastric varices
Patients with gastric varices often have a gastro-renal shunt. A balloon catheter can be used to occlude this shunt and then a sclerosant can be injected into the gastric varices. This technique is reported to be close to 100% successful with a low recurrence rate.53,54,55 One of the complications with BRTO is possible aggravation of oesophageal varices secondary to occlusion of the gastrorenal shunt. However, data again remain limited, and the technique should be compared with other more established treatments for gastric varices. In a small series, BRTO was compared with TIPSS in patients with active gastric variceal bleeding.56 There was no difference in terms of immediate haemostasis, rebleeding and encephalopathy. Interestingly, BRTO resulted in a significant decrease in Child’s score.
Prevention of variceal rebleeding
Following the index oesophageal variceal bleed, the majority of patients will rebleed, most commonly within the first six weeks.57,58 Clinical risk factors for early recurrence of variceal bleeding include a severe index bleed, presence of encephalopathy, advanced liver disease and renal impairment.59 The endoscopic predictors of early rebleeding are active bleeding at initial endoscopy, stigmata of recent bleeding and large varices.16,59 Improvement of liver function may decrease the the risk of rebleeding, therefore, it is important to stress abstinence in patients with alcoholic liver disease. Due to the high risk of rebleeding, all patients with a variceal bleed should be enrolled in a secondary prophylaxis programme. (Fig I)
Pharmacologic therapy
The most commonly used pharmacologic agents for secondary prophylaxis of variceal bleeding are nonselective beta blockers. They have been shown to reduce the risk of rebleeding and improve survival. A meta-analysis showed a 20% reduction in variceal rebleeding and a 5.4% improvement in the mean survival rate at two years.60Accordingly, five patients would need to be treated with beta-blockers to prevent one rebleeding episode and 13 to prevent one death from rebleeding. However, one of the major limiting factors of beta blockers is their tolerability and side effects. The addition of nitrates to beta blocker may further decrease the recurrence of variceal bleeding, especially in patients younger than 50 years, but this does not improve survival.61 The combination of beta blocker and nitrate has been shown to be better than endoscopic sclerotherapy in patients with Child’s A or B cirrhosis.62The only randomized trial to compare this combination therapy versus beta blocker alone also showed the combination to be more effective.61 One of the studies showed that if beta blocker alone did not improve haemodynamics, i.e. decrease HVPG measurement to <12mmHg or <20% of baseline, addition of nitrates may result in improved haemodynamics resulting in lower incidence of first variceal bleeding or rebleeding.63
Endoscopic therapy
This is currently the most widely used method for preventing oesophageal variceal rebleeding. A meta-analysis of eight trials showed reduction in rebleeding with endoscopic sclerotherapy compared with no active treatment.64 A metaanalysis of nine trials showed sclerotherapy to be more effective than beta blockers in preventing variceal rebleeding.65 However, the incidence of adverse effects was significantly higher with sclerotherapy favouring the use of beta blockers for prevention of variceal rebleeding. There was no difference in survival.
VBL is now the endoscopic treatment of choice for secondary prophylaxis. It is associated with lower risk of recurrent bleeding, fewer complication and better survival than sclerotherapy and requires fewer sessions.37,66,67 It should be performed every one to two weeks until eradication of varices. Thereafter, periodic endoscopic surveillance is necessary. This is particularly important because there appears to be a higher rate of variceal recurrence with VBL compared with sclerotherapy. VBL has also been compared with pharmacotherapy in prevention of variceal rebleeding. A study showed VBL to be more effective than combination therapy with a beta blocker and nitrate in preventing recurrent bleeding from oesophageal varices with similar complications and survival.68 Anotherstudy showed that medical therapy (beta blocker ± nitrate) was equivalent to VBL in preventing oesophageal variceal rebleeding with no survival difference.69 However, in thisstudy, all patients were subjected to HVPG measurement at baseline, at three months (drug therapy arm) and at yearly intervals (all patients). A third study found this combination of drug therapy was more effective than VBL for prevention of recurrent bleeding with a lower rate of complications.70This study also used HVPG measurement to guide drug therapy. On balance, combination drug therapy appears to be at least as good as VBL if HVPG is monitored. However, without HVPG measurement, VBL is probably superior in the prevention of rebleeding.
Combined modality therapy
Combined sclerotherapy and beta blocker therapy decreases the rate of recurrent bleeding compared with beta blocker alone but there was no survival benefit.71,72 The combination of VBL with beta blocker and sucralfate was found to be more effective than VBL alone for reducing rebleeding.73A number of studies have compared combined VBL and sclerotherapy with VBL alone. A recent meta-analysis of seven randomized controlled trials suggested that the combination therapy had more complications without any definite reduction in rebleeding or mortality.74 Therefore,VBL alone is the endoscopic treatment of choice for the prevention of variceal rebleeding. Two recent studies have compared combination of VBL followed by endoscopic induction of mucosal fibrosis by Argon Plasma Coagulation (APC) versus VBL alone in eradication of oesophageal varices.75,76 The addition of APC post VBL appears to reduce variceal recurrence with few significant side effects. Further studies using APC are required to assess this approach.
TIPSS
There are at least 14 randomized clinical trials and two meta-analysis comparing endoscopic therapy with TIPSS for the prevention of oesophageal variceal rebleeding. These studies report a significant reduction in rebleeding rates with TIPSS. However, TIPSS led to an increased incidence of encephalopathy with no survival benefit. TIPSS has also been compared with combined propranolol and isosorbide- 5-mononitrate in Child B/C patients in a randomized control trial.77 This revealed that combination medical therapy wasless effective than TIPSS in preventing rebleeding (49% vs. 13%), but led to less encephalopathy (13% vs. 38%). The two year survival probability was identical (72%) and the identified cost of TIPSS was twice that of medical therapy. A randomized controlled trial has compared TIPSS followed by VBL against TIPSS with long term portographic surveillance.78 This showed that VBL following TIPSS is asuitable alternative to long term TIPSS surveillance with comparable rebleeding rates and mortality and has the advantage of significantly lower incidence of encephalopathy.
The major complications associated with TIPSS are shunt dysfunction and encephalopathy. Primary shunt patency rate is 45.4% at one year and 26% at two years50 and requiresregular surveillance by doppler ultrasound or direct portography. However the recent development of covered stents should greatly reduce the incidence of shunt dysfunction. Encephalopathy is more likely to occur in patients with previous encephalopathy, severe liver disease and in the elderly.79,80
In view of the published data, the role of TIPSS in the prevention of recurrent oesophageal variceal bleeding remains as a second line treatment for patients who have recurrent bleeding despite endoscopic therapy. However, local expertise and resources may affect management decisions.
Surgery
Surgical portocaval shunts have been shown to decrease the rate of rebleeding but increase encephalopathy compared with endoscopic therapy64. More selective shunts, such as adistal splenorenal shunt, have the advantages of preserving liver function and limiting encephalopathy. In addition, they do not preclude potential future liver transplant. The role of surgery in the prevention of variceal rebleeding is generally limited to Child A cirrhotic patients who do not respond to endoscopic/pharmacologic therapy. The choice of either TIPSS or surgery in this scenario depends on the patient’s condition and local expertise.
Primary prophylaxis of variceal haemorrhage
One third of cirrhotic patients with varices will bleed from their varices.2,3 There is good evidence showing the benefit of prophylactic therapies in this situation. Therefore, it is important to screen all cirrhotics for varices. The BSGGuidelines recommends primary prophylaxis for all cirrhotic patients with grade 3 varices and for patients with Child class B or C disease with grade 2 varices.22
Pharmacologic treatment
Several randomized controlled trials and meta-analyses have demonstrated the efficacy of nonselective beta blockers in reducing the rate of index variceal bleed by almost 50%, with a trend towards improved survival.81,82 When compared with sclerotherapy and shunt surgery, propranolol was the only cost effective therapy for primary prophylaxis.83The addition of isosorbide mononitrate to beta blocker therapy may offer additional protection against variceal bleeding if tolerated or if it results in improved haemodynamics.63,84 However, nitrates alone have not been shown to be more effective than placebo when used in patients intolerant of beta blocker.85
Endoscopic therapy
A review of nineteen trials on the use of sclerotherapy for primary prophylaxis drew no firm conclusions because the groups were too heterogenous.64 It is generally acceptedthat the risks and complications preclude the use of sclerotherapy for primary prophylaxis of variceal bleeding. More recently, VBL has been assessed in a number of studies for this role. A study showed VBL to be equivalent to propranolol but superior to nitrates in preventing first variceal bleeding.86 A meta-analysis comparing VBL with placebo and beta blockers for primary prophylaxis showed that VBL reduced the risk of bleeding, bleeding related mortality and overall mortality when compared with placebo. When VBL was compared with beta blockers, the rate of first bleed was reduced but there was no difference in mortality.87 Therefore, prophylactic variceal ligation is generally reserved for patients who do not tolerate nonselective beta blockers or for those in whom compliance with drug therapy is unlikely.
Conclusion
Variceal bleeding remains a challenging clinical emergency. We now have improved pharmacological, endoscopic and radiological techniques to control bleeding and to reduce rebleeding. Prophylactic antibiotics should be given to all cirrhotic patients with gastrointestinal bleeding as they improve survival. Beta-blockers and VBL are also effective primary prophylactic therapies for variceal bleeding. Therefore, all cirrhotic patients should be endoscoped to identify those at risk of bleeding.
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