| Abstract|| |
Several methods have been used to treat acute variceal hemorrhage. Sclerotherapy is the method of choice. The use of vasoactive drugs is popular despite unsatisfactory effect and systemic hemodynamic adverse effects. The recently introduced longacting somatostatin analogue, octreotide, is more effective and has no systemic adverse effects. It may be used while waiting for emergency sclerotherapy or in combination with sclerotherapy in patients with high risk of rebleeding.
|How to cite this article:|
Beauchant M. Vasoactive drugs in the management of acute variceal bleeding. Saudi J Gastroenterol 1997;3:3-7
The first month mortality of acute variceal bleeding remains still high (20-25%)  despite the widely use of emergency sclerotherapy as the first-choice treatment. More recently, endoscopic variceal ligation appeared safer than sclerotherapy, but no controlled trials in acute bleeding have been reported so far. In European countries, bleeding rarely occurs from fundal varices (1-3%), hence few retrospective studies are available which suggested that the best treatment should be also sclerotherapy but using a glue , . However, these endoscopic techniques require the presence of an experienced endoscopist at anytime in the emergency care unit. Thus an increasing number of randomized trials dealing with the use of vasoactive drugs alone or in combination with endoscopic therapy or balloon tamponade has been reported. We wish to review the latest developments in the medical therapy of acute variceal bleeding.
In clinical practice, three important periods should be distinguished. The first one corresponds to the emergency control of bleeding and takes place during the first 12 or 24 hours. The vast majority of the randomized trials dealt with this critical period. However, the numerous studies performed are not easy to interpret because of the heterogeneous criteria used even on the same treatment and sometimes because of the inadequacy of end points and study power  . The second period corresponds to the prevention of early rebleeding and lasts for the first five to seven days after the occurrence of index bleeding. Very few studies dealt with this period, although rebleeding is a major cause of death. The third period corresponds to the prevention of late rebleeding, and actually there seems to be a trends in favor of band ligation over propranolol, sclerotherapy or a combination therapy , .
Among the various treatments used, balloon tamponade is the oldest one. In randomized and retrospective studies the 24-hour bleeding control rate reached usually 90%, but when the balloons were deflated, rebleeding occurred in up to 50% of the patients  . This method is also associated with fatal complications such as inhalation pneumonia or esophageal perforation  . This method is usually used only when endoscopic and vasoactive drug therapy proved to be a failure, and in the case of cataclysmic hemorrhage  . These circumstances represent probably less than 10% of cases. Sclerotherapy is clearly the best treatment and has been shown to be significantly more effective than balloon tamponade or vasopressin infusion even combined with nitroglycerin , . However, emergency sclerotherapy is not available in all the centers. This is the main reason why vasoactive drugs remain popular throughout the world, despite their high costs. Vasopressin is the oldest vasoactive drug used in emergency. Its rate of efficiency hardly reached 70% in randomized studies  . Despite the addition of nitroglycerin, severe side effects still remain ranging from myocardial infarction to cerebrovascular accidents  . We suggest that this combination should no longer be used. Terlipressin is a vasopressin analogue which is associated with less severe side effects than vasopressin . It has been shown to be as effective as balloon tamponade and more effective than vasopressin  .
More recently two major vasoactive drugs emerged: somatostatin and its long acting analogue octreotide. The mechanisms of action of these drugs remain controversial. In human and animal experiments, both drugs decreased portal pressure, portal blood flow and mainly azygos blood flow through a decrease of vasoactive peptide secretion such as glucagon or vasoactive intestinal peptide which play a major role in the hyperkinetic syndrome of portal hypertension ,,, . Their effects on variceal pressure are however weak , . Recently, two interesting hypothesis have been advocated. In a still unpublished study, we observed that octreotide infusion led to a significant increase of the lower esophageal sphincter (LES) pressure in cirrhotics. Other drugs such as metoclopramide have the same effect, and had been used for variceal bleeding  . This increase in LES pressure may theoretically decrease the blood flow through the perforating veins of the lower esophagus which feed the varices. Another interesting hypothesis is that, like a meal, the presence of blood in the intestine leads to a splanchnic hyperemia in cirrhosis  . This probably may account for early rebleeding. In Doppler ultrasonography studies, octreotide has been shown to blunt the meal induced increase in blood flow and portal pressure  . In an animal experiment, over transfusion also led to an increase in portal blood flow and octreotide infusion was the only vasoactive drug which was able to prevent this increase  . Finally, the main advantage of somatostatin and octreotide is the absence of systematic side effects although the use of bolus or high dose of octreotide have been associated with a weak but significant decrease of heart pulse rate and a weak increase of arterial and right atrial pressure  . In clinical studies, unlike vasopressin or terlipressin, withdrawal of both drugs had never been required for adverse effects  .
Somatostatin has been shown to be as effective as vasopressin, terlipressin, balloon tamponade or sclerotherapy  . In a placebo controlled study  no significant beneficial effect was obtained, but the too high bleeding control rate in the placebo group (86%) suggested a major bias. In the prevention of early rebleeding, somatostatin was clearly more effective than placebo and as effective as sclerotherapy ,, .
No placebo controlled studies have been done with octreotide. This drug was shown to be as effective as vasopressin and balloon temponade , . In a previous trial, octreotide was found to be associated with a higher success rate than terlipressin, and this result was associated with a reduction of transfusion requirements and fewer side effects at a lower cost  . Octreotide is as effective as sclerotherapy  . However, when vasoactive drug infusion is stopped, rebleeding is often observed in up to 27% of cases at the end of the first 48 hours  . Rebleeding rate is also usual during the first five days after emergency sclerotherapy  or ligation  . This clearly indicates that a combination therapy is necessary in order to limit these rebleeding incidences.
Few studies dealt with combined therapies in the literature. Avgerinos et al  showed that somatostatin combined with balloon tamponade was not more effective than each treatment alone, like terlipressin in another trial  . In a more recent open trial, terlipressin given from third day to seventh day after emergency sclerotherapy significantly prevented rebleeding during this period  . We conducted a prospective, double-blind, randomized trial, which compared sclerotherapy alone with a combination of sclerotherapy and octreotide for the control of acute variceal bleeding and the prevention of early rebleeding in patients with cirrhosis  . Emergency sclerotherapy was performed using 2% polidocanol without exceeding a 20 ml total injection. Then the patients were randomized to receive either a continuous injection of a placebo, or octreotide at a 2511 g/h infusion rate for five days. The primary outcome was the bleeding control rate at five days assuming that all deaths occurring during this period should be considered as failure of treatment whenever the cause of death as stated in a recent consensus workshop  . In this study, most of the deaths were related to uncontrolled bleeding (6/10 in the placebo group and 5/7 in the octreotide group). During a two-year period, 199 patients were enrolled. At five days, the bleeding control rate was significantly higher in the octreotide group compared to the placebo group independently of child's grade. The difference remained significant at 15 and at 30 days, but the first month cumulative survival remained unaffected.
A logistic regression analysis indicated that the factors independently associated with bleeding control at five days were octreotide infusion and the number of units of blood transfused before the assigned treatment. The latter variable was negatively correlated with success and positively correlated with child's class. We also performed a statistical analysis in the placebo group only and we found that the time lapse between occurrence of bleeding and therapy played a major role in the success rate, although this parameter had no predictive value in the octreotide group. This may help to select a group of patients where the combination therapy is needed: patients admitted lately and who received blood transfusion prior to emergency sclerotherapy.
Variceal ligation is also an effective way to control variceal bleeding. Sung et al.  recently published the results of an open trial to evaluate the effect of combining octreotide and variceal ligation. Initial hemostasis was identical in both groups (95%) but 38% in the control group had recurrent bleeding compared to only 9% in the combined therapy group. This study clearly confirmed our results.
Some authors demonstrated that octreotide given subcutaneously for the prevention of late rebleeding was not beneficial  . However they used a too low dose of octreotide. Phannacokinetic data suggested that a 5O0µ g dose every eight hours would probably be necessary which is quite expensive  .
In conclusion, among the vasoactive drugs, octreotide has no systemic side effects and it can be used very early when waiting for emergency sclerotherapy. A combination therapy is needed especially in patients with high risk of early rebleeding. TIPS should be limited to uncontrolled rebleeding. despite repeated sclerotherapy or ligation sessions, especially in patients waiting for liver transplant. The place of balloon tamponade or emergency surgery is probably very limited.
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Hepatology Unit, BP 577 86021, CHU Poitiers
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