Variceal bleeding, due to portal hypertension, is an important complication of liver cirrhosis, occurring in 20–70% of the patients. The variceal bleeding recurrence rates are above 70%, with a 2 year-mortality rate of over 60%^{1, 2)}. The management of variceal bleeding is aimed at control of acute bleeding and the prevention of rebleeding. Methods of treatment that consist of decompression therapy of portal pressure and a local hemostatic therapy have been used. Standard therapies used for variceal bleeding include sclerotherapy or ligation therapy combined with a vasoconstrictor. Pharmacological therapy for the early treatment of variceal bleeding reduces the portal pressure, which in turn decreases rebleeding and stabilizes the patient enabling local therapy for varix to be performed. Single therapy with vasopressin infusion or the combination therapy of vasopressin and nitroglycerin are usually used to control of variceal bleeding, and reduce the splanchnic blood flow and a portal pressure, resulting in a hemostatic effect for the acute bleeding. The efficacy of drug therapy is about 50%, with reported systemic side effects in 25%^{3, 4)}. Somatostatin is a peptide, containing 14 amino acids, which reduces the splanchnic blood flow and hepatic venous pressure, and has been used for the treatment of variceal bleeding. It has been reported as the drug that has the lowest side effects as it acts mainly on the splanchnic blood flow^{5, 6)}. A prospective randomized controlled clinical trial was conducted to compare the effectiveness of somatostatin and vasopressin for the control of active variceal bleeding in patients with liver cirrhosis.

Between March 1997 and April 1999, 43 patients were admitted to the Chungnam National University Hospital or the Youngnam University Hospital for the treatment of acute variceal bleeding. Patients were included in the study if they met the following conditions; they were aged between 18 years and 70 years, had hematemesis or proven bleeding by gastric lavage, had moderate to severe bleeding, which required a transfusion of above 500 mL of blood, and with variceal bleeding confirmed by endoscopy before or after the drug infusion (somatostatin or vasopressin). Other patients were excluded from the study for the following conditions; their age was below 17 or above 71 years, they had mild bleeding, needed an emergency operation for severe bleeding, had had a previous decompressive operation of portal pressure, had another coagulopathy, with the exception of liver disease, had a systemic disease (cardiovascular, respiratory, renal, neurologic disease) or had received a therapeutic endoscopy within 6 hours following the drug infusion.

Selected patients were evaluated for their vital signs, CBC, prothrombin time, liver function, degree of hemorrhage and Child-Pugh classification before the drug infusion. Variceal bleeding was confirmed by endoscopy either before or after the drug infusion. The informed consent was obtained from each patient, or a relative, after a full explanation of the nature and purpose of the study. The patients were randomized, using a table of random numbers, to receive either vasopressin or somatostatin. The vasopressin was given as a continuous intravenous infusion, at a rate of 0.4 IU per min for 48 hours, and the somatostatin was administered as a continuous intravenous infusion, following a 50 mcg bolus, at a rate of 250 mcg per hr.

Over the initial 5 day following admission, the vital signs were checked every 2–4 hours after a trial drug infusion, and a nasogastric tube was kept in place to check for rebleeding and the CBC and prothrombin time also checked. The side effects associated with the drug infusion were observed, and endoscopic ligation therapy or sclerotherapy were carried out after the trial of drug infusion.

During the drug infusion, following conditions regard as absence of rebleeding; the systolic blood pressure was maintained above 80 mmHg, with the reduction in the systolic blood pressure being no more than 20 mmHg, the increase in the pulse rate was no more than 20 beats/min, the hematocrit was kept above 9 g/dL, with a reduction of no more than 1 g/dL and here was no evidence of fresh blood via the nasogastric suction. During the 5 days’ trial of drug administration, the early rebleeding and side effects had been examined and then evaluated. Paired t-and chi-squared tests were used for the statistical analysis of the results.

Portal hypertension and varix occured in 50–70% of the cirrhotic patients, with variceal bleeding occurring within 2 years in 30% of the patients with varices^{7, 8)}. Both medical and surgical therapies exist for the managements of the variceal bleeding. The medical therapy is composed of endoscopic treatments, mechanical coagulation using a Sangstaken-Blakemore tube and pharmacological agents, such as vasoconstrictors and nonselective beta receptor blockers. Other methods for the managements of variceal bleeding are a surgical operation and transjugular intrahepatic portosystemic shunt (TIPS).

Endoscopic sclerotherapy has been shown to have a high control rate of variceal bleeding when the sclerosant (ethanolamine oleate or polidocanol) was directly injected into the varices, with an alternative technique involving a submucosal injection adjacent to the varices. Repeated endoscopic sclerotherapy has excellent effects, these being complete remission and the prevention of rebleeding⁹⁾.

Since Stiegmann and colleagues first carried out endoscopic ligation therapy, endoscopic ligation has been broadly used for variceal bleeding. This method involves the aspirations with a vacuum, and mechanical ligations with ‘O’ shaped rubber bands. Compression with the rubber band induces a necrosis of ligated tissue, shallow ulceration, fibrosis and scar formation. Endoscopic variceal ligation therapy has shown excellent results¹¹⁾. Compared with sclerotherapy, endoscopic ligation shows no differences in hemostatic, rebleeding and survival rates, but tends to be simpler and lower complication rates¹²⁾. These two endoscopic therapics achived hemostasis and prevention of rebleeding in 85–95% of patients.

Many drugs have been used for the treatment of variceal bleeding. Of these β-blockers are useful for the long-term preventive therapy of variceal bleeding¹⁵⁾. With acute bleeding, vasoconstrictors have been used to facilitate sclerotherapy and the surgical treatment for this condition^{16, 17)}. Vasopressin, which constricts the visceral arteries and reduces the splanchnic blood flow, has been used, and consequently this drugs decompresses the portal pressure and has hemostatic effects on variceal bleeding.

The effectiveness of vasopressin for acute variceal bleeding is about 50%, but major adverse effects, such as myocardial infarction and systemic adverse effects, have been noted, which are still areas of debate^{3, 4, 16, 17)}. Somatostatin inhibits the secretion of growth hormone and most gastrointestinal, hormones, but has an effect in the treatment of variceal bleeding by reducing the splanchnic blood flow in patients with liver cirrhosis as also as in normal subjects^{5, 6, 19, 21, 22)}. This reduction in the splanchnic blood flow leads to a significant falling of the portal pressure, but does not induce alterations in the systemic hemodynamics which results in the advantage of the diminution of the systemic adverse effects differently to vasopressin^{5, 6, 20–22)}.

Sonnenberg et al²⁰⁾ reported that the reducing effect of somatostatin on the portal pressure was significantly less than that of vasopressin, and had no effect unless somatostatin was infused as an initial bolus injection. Raptis et al^{23, 24)} has reported the failure to control esophageal bleeding. Conversely, Jenkins et al²⁵⁾ and Bagarani et al²⁶⁾ have reported the excellent effect of somatostatin on esophageal variceal bleeding, and also Kravetz et al²⁷⁾ reporting that somatostatin was as effective as vasopressin in the control of variceal bleeding.

This study was a prospective randomized study for the comparison of the effectiveness and complication rates of somatostatin and vasopressin infusions as pharmacological therapies for the treatment of acute variceal bleeding. Rebleeding within 6 hours after the beginning of the therapy was observed in 3 of the 23 patients (13.0%) receiving vasopressin and in 1 of the 20 (5.0%) receiving somatostatin, but there was no significant difference between the two groups (p>0.05). The initial hemostatic effects, which prevented rebleeding within 6 hours of therapies, were noted in 87.0 and 95.0% of the vasopressin and somatostatin infusion groups, with both drugs achieving high rates for the control of bleeding during the early post-bleeding stages. The initial hemostatic effects in the present study were higher than those of Jenkins et al²⁵⁾, Bagarani et al²⁶⁾ and Kravet et al²⁷⁾, who reported 28–74 and 45–85% in the vasopressin and somatostatin infusion groups, respectively. The reason for the rebleeding in some patients during therapy, after the initial control of bleeding, has been reported to be due to drug resistance, but this is still unclear.

In this study, most of the patients had been examined with therapeutic endoscopy, such as endoscopic variceal ligation or endoscopic intravenous injection of a sclerosing agent (histoacryl), from 6 hours after the drug infusion. Somatostatin or vasopressin were infused for 48 hours, and the patient’s hospital course relating to these drugs observed, but it was unclear whether the therapeutic endoscopy and the duration of the drugs administration had any effects on occurrence of rebleeding.

Five of the 23 patients (21.7%) receiving vasopressin, and 5 of the 20 (25.0%) treated with somatostatin, re-bled during the initial 5 days following the therapy, but with no significant difference (p>0.05), which was similar to the results of other reports^25–27). In this study, the administration of somatostatin and vasopressin, within 6 hours and for the initial 5 days following the infusion, had similar hemostatic effects.

Mild complications, such as bradycardia and elevation of blood pressure, during the treatments were observed in 5 (21.7%) and 6 (30.0%) patients in the vasopressin and somatostatin groups respectively, but with no significant difference. Cardiovascular and gastrointestinal ischemic complications, such as chest and abdominal pains which required nitroglycerin, were observed in 5 of the patients treated with vasopressin, but not found in the somatostatin group. The somatostatin infusion group had a lower rate of associated significant complications than the vasopressin infusion group, which was no different from the results in other studies^25–27). These lower rates of induced complications are thought to be due to the more selective action of the somatostatin on the splanchnic vascular bed^{5, 6, 20–22)}. This suggests that the complications of vasopressin could be reduced by decreasing the dose and length of the infusion or the simultaneous administration of nitroglycerin⁴⁾.

In this study, two patients in the vasopressin and one in the somatostatin groups died due to uncontrolled rebleeding during trial, with one of the vasopressin group dying due to hepatic failure 2 weeks later after therapy. Three of the patients who died were included in Child-Puch class C group, with this group also having a higher mortality rate in previous studies^25–27).

In conclusion, this study has shown that somatostatin and vasopressin were no different in the prevention of rebleeding due to acute variceal bleeding, but that somatostatin had a lower risk of the serious complications.