Effects of somatostatin, terlipressin and somatostatin plus terlipressin on portal and systemic hemodynamics and renal sodium excretion in patients with cirrhosis

BACKGROUND AND AIM: Terlipressin and somatostatin are the most preferable agents for the control of variceal bleeding in cirrhotic patients. The present study evaluated the hemodynamic effects of somatostatin, terlipressin and somatostatin plus terlipressin in cirrhotic patients with portal hypertension, as well as the effect of each regimen on renal sodium excretion. METHODS: Twenty-four patients with esophageal varices were randomly assigned to receive either an intravenous infusion of a placebo (n = 12) or somatostatin 250 microg/h after an initial bolus of 250 microg (n = 12) for 60 min. Thereafter, each patient received an intravenous injection of terlipressin 2 mg while the intravenous infusion of either somatostatin or placebo was maintained. Portal and systemic hemodynamic parameters, assessed by Doppler sonography, and urinary sodium excretion were evaluated at baseline, 60 min after placebo or somatostatin, and 30 min after terlipressin. RESULTS: Placebo had no effect on the patients studied. After terlipressin, portal vein velocity, portal flow volume and cardiac output (CO) significantly decreased (0.09 vs 0.15 m/s, 0.56 vs 1 L/min and 6.4 vs 7.6 L/min, respectively [values are medians]), while mean arterial pressure (MAP) and systemic vascular resistance significantly increased (103.3 vs 89.9 mmHg and 1541 vs 1108dyn.s/cm(5), respectively). Fractional sodium excretion significantly increased in patients without ascites (0.43 vs 0.16%) while it did not change in patients with ascites. Somatostatin did not alter portal hemodynamics whereas it significantly reduced MAP, heart rate (HR) and CO (86.9 vs 98.6 mmHg, 65 vs 73 bpm and 8.4 vs 9.1 L/min, respectively) and, in patients with ascites, sodium excretion (0.13 vs 0.23%). The addition of terlipressin to somatostatin induced similar changes to those observed after terlipressin alone. The magnitude of increase in MAP was significantly higher in patients receiving terlipressin alone than in those receiving somatostatin plus terlipressin (15 vs 5.3%), while CO was conversely affected (-28.5 vs-20.9%). CONCLUSIONS: Combined treatment with somatostatin and terlipressin does not exert an additive portal hypotensive effect in cirrhotic patients as compared to terlipressin alone, whereas somatostatin alone may impair systemic hemodynamics. Compared with somatostatin, terlipressin exerts a more beneficial effect on renal sodium excretion in patients with or without ascites.     

A multicenter, randomized, double-blind trial of somatostatin in the management of acute hemorrhage from esophageal varices

A prospective, randomized, placebo-controlled, double-blind, multicenter clinical trial of intravenous somatostatin (Stilamin; Serono Laboratories, Inc., Randolph, MA) was performed in 102 patients with actively bleeding esophageal varices from August, 1985, to November, 1986. Patients had major hemorrhage indicated by hematemesis or melena and evidence of significant blood loss. For entry, patients had to have endoscopic demonstration of active bleeding from esophageal varices or stigmata of recent hemorrhage and bright red blood in the gastric aspirate with no other source of bleeding found. Randomized patients received identical-appearing somatostatin or placebo for a 30-hr study period. Those given somatostatin received a 250-micrograms bolus and a 250-micrograms per hr infusion with repeat bolus and doubling of the infusion if the bleeding was not controlled. In retrospect, 18 patients could not be evaluated. Of the 84 evaluable patients, 48 received somatostatin and 36 placebo. They were comparable in age, gender, severity of liver disease and history of variceal bleeding. Transfusion requirements were similar in both groups. Bleeding stopped for 12 consecutive hr during 30 hr of the study period in 31 (65%) of the somatostatin group vs. 30 (83%) of the placebo group (p = 0.06). The median time to cessation of bleeding was 2 hr in the placebo group and 3 hr in the somatostatin group. Deaths following the study period were nine (25%) in the placebo group and 15 (31%) in the somatostatin group. Within the limitations of the present study, we conclude that somatostatin was ineffective in the management of active bleeding of esophageal varices.     

Different haemodynamic effects of a single dose of long-acting isosorbide-5-mononitrate in healthy subjects and patients with cirrhotic portal hypertension

BACKGROUND: The action pathways of nitrates are hypothesised to be deranged in cirrhosis. AIM: In order to confirm it, the acute haemodynamic effects of isosorbide-5-mononitrate in cirrhotic patients and controls was investigated. PATIENT: Nine cirrhotics and nine healthy controls. METHODS: Evaluation in the fasting state, 90 min after isosorbide-5-mononitrate or placebo (double-blind on two different days) and then 30 and 120 min after eating a standard meal. Various systemic and splanchnic haemodynamic parameters, including arterial impedance, assessed as Doppler pulsatility index, were measured. RESULTS: isosorbide-5-mononitrate reduced arterial pressure and increased heart rate and mesenteric pulsatility index both in controls and in cirrhotics, whereas the following parameters behaved differently in the two groups (P < 0.05): hepatic pulsatility index decreased (-9%) and the portal velocity increased (+13%) in controls, whereas hepatic pulsatility increased (+18%) and portal velocity decreased (-18%) in cirrhotics. The two groups presented a similar pattern of changes in most variables under placebo after a meal. In controls, the administration of isosorbide-5-mononitrate blunted the postprandial mesenteric vasodilation and related changes in splanchnic and systemic circulation, expected at 30 min, in comparison to those observed under placebo. In cirrhotics, instead, the postprandial pattern was similar under placebo and isosorbide-5-mononitrate. CONCLUSIONS: The acute administration of isosorbide-5-mononitrate produces different haemodynamic effects in healthy and diseased livers, both in the fasting state and after a meal, consistent with the hypothesis of a deranged response of the intrahepatic microcirculation to nitrates in cirrhosis.     

Erythromycin infusion prior to endoscopy for acute upper gastrointestinal bleeding: a randomized, controlled, double-blind trial

BACKGROUND/AIM: Presence of clots in the stomach makes emergency endoscopy difficult in patients with upper gastrointestinal bleeding. We investigated whether the association of erythromycin infusion to gastric lavage could improve stomach cleansing before endoscopy. PATIENTS AND METHODS: One hundred patients admitted for upper gastrointestinal bleeding were randomly assigned to receive either gastric lavage plus intravenous erythromycin (250 mg) or gastric lavage plus placebo before endoscopy in a double-blind study. The primary end point was the efficacy of intravenous erythromycin to improve stomach cleansing before endoscopy, assessed by both subjective and objective criteria. RESULTS: Characteristics of patients at admission were similar in both groups. Sixty-six patients had portal hypertension. The gastric mucosa was entirely visualized by the endoscopist in 65% of patients in the erythromycin group, versus 44% in the placebo group (p<0.05). The quality of examination of the upper gastrointestinal tract, assessed by using a 10-cm visual analog scale, was better in the erythromycin group (4.2+/-2 vs. 3.3+/-2.2, p<0.05). Clots were found in the stomach in 30% of patients in the erythromycin group, versus 52% in the placebo group (p<0.05). However, ability to identify the source of bleeding, mean duration of endoscopy, and need for a second-look endoscopy, did not differ between the two groups. Similar results were observed in the subgroup of cirrhotic patients. Erythromycin was well tolerated by all patients. CONCLUSION: Intravenous erythromycin before endoscopy improves stomach cleansing and quality of endoscopic examination in patients with upper gastrointestinal bleeding, but the clinical benefit is limited.     

Terlipressin vs. somatostatin in bleeding esophageal varices: a controlled, double-blind study.

Fifty episodes of bleeding from esophageal or gastric varices in 33 patients with cirrhosis were randomized to treatment with either intravenous terlipressin (2 mg initially and 1 mg every 4 hr for 24 hr together with bolus injection and continuous infusion of placebo) or with somatostatin (250 micrograms as a bolus and continuous infusion of 250 micrograms/hr somatostatin for 24 hr and placebo injections). Standard therapy with transfusions, fluid and electrolyte correction and lactulose was administered in both groups. In the terlipressin group, 22 of 25 bleeding episodes (88%) were initially stopped by the vasoactive drugs, and in the somatostatin group 19 of 25 bleeding episodes (76%) were initially stopped by the vasoactive drugs. Two of the three bleeding episodes not arrested by terlipressin and five of the six bleeding episodes not arrested by somatostatin were controlled by balloon tamponade. In one patient in each group variceal bleeding initially could not be stopped, and the patients died. The failure rate of the vasoactive treatment alone, including rebleeding episodes within the study period, was 20% in the terlipressin group and 32% in the somatostatin group. The control rate, including balloon tamponade, was 96% in both groups. The hospital mortality rate was 16% (4 of 25) in the terlipressin group and 24% (6 of 25) in the somatostatin group. Blood transfusions, use of balloon tamponade and duration of bleeding did not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Somatostatin and ranitidine in the treatment of non-variceal upper gastrointestinal bleeding: a prospective, randomized, double-blind, controlled study

BACKGROUND/AIMS: The aim of this study was to compare the efficacy of somatostatin vs. ranitidine in controlling acute non-variceal gastrointestinal bleeding. METHODOLOGY: A total of 48 patients with acute upper gastrointestinal bleeding due to duodenal or gastric ulcer were divided into 2 groups. Group I consisted of 15 patients with Forrest IB and Group II consisted of 30 patients with Forrest II. Two regimens were randomly allocated to all patients within half an hour after the endoscopic procedure: 1) somatostatin-UCB 250 mcg i.v. bolus followed by continuous i.v. infusion at a rate of 6 mg/d for 72 h, or 2) ranitidine 300 mg/d by continuous i.v. infusion for 72 h. RESULTS: In Group I, although mean blood transfusion requirements (no. of units) were lower in patients treated with somatostatin than in those treated with ranitidine, this was not statistically significant (mean +/- SD: 2.56 +/- 3.05 vs. 5.17 +/- 4.96, respectively; P > 0.05); the time of bleeding stop was shorter in the somatostatin group than in the ranitidine group (mean +/- SD: 3.24 +/- 2.45 vs. 11.25 +/- 11.63, respectively; P = 0.0383). The rebleeding and the mortality rates did not differ between the treatment groups in both Group I and Group II. CONCLUSIONS: Somatostatin is more effective than ranitidine in controlling acute non-variceal gastrointestinal bleeding in patients with Forrest IB bleeding activity. Somatostatin has no additional benefit in those with Forrest II bleeding activity.     

A prospective randomized trial comparing somatostatin, balloon tamponade and the combination of both methods in the management of acute variceal haemorrhage.

The aim of this study was to compare the efficacy of: (i) somatostatin infusion, (ii) balloon tamponade with the Sengstaken-Blakemore tube and (iii) the combination of both methods, in the management of acute variceal haemorrhage. Ninety-two consecutive patients with liver cirrhosis who proved to have active variceal bleeding on emergency endoscopy were studied. Thirty-one patients were randomly assigned to an intravenous infusion of 250 micrograms/h of somatostatin (Group I), 30 to the Sengstaken-Blakemore tube (Group II) and 31 to the combination of both methods (Group III). Somatostatin was administered for 24 h, while the gastric and esophageal balloons remained inflated for 48 and 24 h, respectively, then deflated. Patients were under observation for a further 24-h period after withdrawal of treatment. If bleeding recurred, the same treatment was repeated in each group. Following treatment the bleeding was controlled initially in 22 patients (71%) in Group I, in 24 (80%) in Group II and in 25 (80.6%) in Group III. In Group II a significantly (p less than 0.05) higher proportion of patients (14/24) rebled as compared to Groups I (5/22) and III (6/25). Bleeding was controlled following retreatment in four, ten and five patients of the three respective groups. There were marked differences, in the number of complications noticed with each form of therapy. Only three patients (9.7%) in Group I developed complications (p less than 0.05) as compared to ten (33%) in Group II and ten (32%) in Group III. Hospital mortality in all three treatment groups was not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of oral isosorbide 5-mononitrate on mortality following acute myocardial infarction: A multicentre study

We have conducted a randomized, double-blind, placebo-controlledmulticentre trial of oral isosorbide 5-mononitrate (ISMN) in360 patients with suspected acute myocardial infarction. Patientswere stratified prior to analysis according to the presenceor absence of left ventricular failure on admission. ISMN causeda significant reduction in systolic and diastolic blood pressureduring the first 12 h. There was no significant effect on heartrate.Overall mortality was 4-9% in the ISMN group compared with40% in controls at 5 days, and 141% compared with 10-5% at 6months (NS). A non-significant reduction in mortality in theISMN group with heart failure (ISMN 7-9%, placebo 12-9%, at5 days) contrasted with a non-significant increase in mortalityin patients without heart failure treated with ISMN (ISMN 4-1%,placebo 2-1%, at 5 days). Lignocaine was used in twice as manypatients in the ISM N group as in placebo group (P<0-0I),both with and without heart failure. Diamorphine usage was similarin the ISMN and control groups.Oral ISMN has similar haemodynamiceffects to intravenous nitroglycerin, and can be of benefitin acute myocardial infarction with heart failure. However,our results question the use of nitrates in acute myocardialinfarction in the absence of heart failure     

Validation of color Doppler EUS for azygos blood flow measurement in patients with cirrhosis: application to the acute hemodynamic effects of somatostatin, octreotide, or placebo.

BACKGROUND: Color Doppler EUS (CD-EUS) allows minimally invasive measurement of azygos blood flow (AzBF) in portal hypertension, but further validation of the method is needed. Because a limited number of patients has been studied, the acute hemodynamic effects of somatostatin and octreotide on AzBF and gastric mucosal perfusion are poorly defined in portal hypertension. METHODS: A double-blind hemodynamic study was designed to assess rapid changes in AzBF over a 60-minute period after intravenous administration of somatostatin, octreotide, and placebo in 30 stable patients with biopsy-proven cirrhosis. AzBF was measured by using both CD-EUS and the invasive thermal dilution technique in the first 10 patients (phase 1). Then, with CD-EUS alone, the hemodynamic study was extended to a further 20 patients (phase 2). In addition, gastric mucosal perfusion changes were assessed by using laser Doppler flowmetry at endoscopy. RESULTS: In phase 1, the 2 methods for AzBF measurement showed significant correlations both for baseline values (r = 0.685) and for AzBF changes over 60 minutes after drug administration (r = 0.733). In phase 2, a reduction was observed in AzBF 10 minutes after octreotide or somatostatin administration (-47% and -23%, p < 0.0001 vs. placebo, p = 0.058 vs. placebo, respectively). After 60 minutes of somatostatin infusion, AzBF increased 27% over placebo values (p < 0.04). Gastric mucosal perfusion was transiently reduced 5 minutes after octreotide or somatostatin (-21% and -32%, respectively, p < 0.02 vs. placebo). CONCLUSIONS: This is the first study to validate CD-EUS AzBF measurement with reference to the invasive thermodilution technique in cirrhosis. It confirmed the transient effects of somatostatin and octreotide on both AzBF and gastric mucosal perfusion. In addition, a significant rebound phenomenon after 60 minutes of continuous intravenous somatostatin infusion was observed.     

Banding ligation versus nadolol and isosorbide mononitrate for the prevention of esophageal variceal rebleeding

BACKGROUND & AIMS: beta-blockers and banding ligation are effective in the prevention of variceal rebleeding. However, the relative efficacy and safety remains unresolved. METHODS: One hundred twenty-one patients with a history of esophageal variceal bleeding were enrolled. Patients were randomized to undergo regular endoscopic variceal ligation (EVL group, 60 patients) until variceal obliteration, or drug therapy by using nadolol plus isosorbide mononitrate (N+I group, 61 patients) during the study period to prevent rebleeding. RESULTS: After a median follow-up period of 25 months, recurrent upper gastrointestinal bleeding developed in 23 patients in the EVL group and 35 patients in the N+I group (P = 0.10). Recurrent bleeding from esophageal varices occurred in 12 patients (20%) in the EVL group and 26 patients (42%) in the N+I group (relative risk = 0.45; 95% confidence interval, 0.24-0.85). The actuarial probability of rebleeding from esophageal varices was lower in the EVL group (P = 0.01). The multivariate Cox analysis indicated that the treatment was the only factor predictive of rebleeding. Treatment failure occurred in 8 patients (13%) in the EVL group and 17 patients (28%) in the N+I group (P = 0.01). Fifteen patients in the EVL group and 8 patients of the N+I group died (P = 0.06). Complications occurred in 17% of the EVL group and in 19% of the N+I group (P = 0.6). CONCLUSIONS: Our trial showed that ligation was more effective than nadolol plus isosorbide-5-mononitrate in the prevention of variceal rebleeding, with similar complications in both treatment modalities. However, there is no significant difference in the survival rate between the 2 groups.     

Nitrates in myocardial infarction: influence on infarct size, reperfusion, and ventricular remodelling.

OBJECTIVE--To assess the possible benefits of intravenous isosorbide dinitrate in acute myocardial infarction and oral isosorbide mononitrate in subacute myocardial infarction. METHODS--316 patients presenting with acute myocardial infarction were entered into double blind placebo controlled clinical trials assessing infarct size by enzyme release, ventricular size and function by echocardiography, reperfusion by continuous 12 lead ST segment monitoring and late potentials by high resolution electrocardiography. RESULTS--301 patients, of whom 292 (97%) received thrombolytic treatment, were randomised on admission to intravenous isosorbide dinitrate or placebo. Overall, there was no significant effect of treatment on infarct size, ST segment resolution, ventricular remodelling, or late potentials at day 3. A trend was observed towards a reduction in infarct size in patients with non-Q wave infarction treated with isosorbide dinitrate. Heterogeneity of nitrate effect was observed in relation to the degree of ST segment elevation on presentation with a clear benefit of isosorbide dinitrate in patients with moderate ST segment elevation (472 U/l v 704 U/l, P = 0.003) and a trend towards a deleterious effect in patients with marked ST segment elevation (1152 U/l v 1058 U/l, P = 0.2). ST segment re-elevation was more common among patients receiving nitrate treatment than in those assigned to placebo (29 v 16, P < 0.05). Some 160 patients underwent a further randomisation to sustained release isosorbide mononitrate or placebo on day 3. Echocardiographic volumes after 6 weeks of treatment were similar in the two groups. CONCLUSIONS--No benefit was observed with administration of nitrates in the treatment groups as a whole for either acute or subacute infarction. There was, however, evidence of heterogeneity of effect in the different subgroups of acute infarction, and the possibility that nitrates may have differing actions in different groups of patients should be considered.     

Can somatostatin prevent post‐ERCP pancreatitis? Results of a randomized controlled trial

BACKGROUND: Acute pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP), occurring in 1-10% of patients. Several substances have been used, with negative results, in an attempt to prevent this complication. METHODS: We performed a double-blind randomized trial in 372 consecutive patients undergoing diagnostic or therapeutic ERCP to evaluate the role of somatostatin in preventing post-ERCP pancreatitis. The first group received continuous somatostatin infusion for 12 h starting 30 min before ERCP, the second group received a bolus intravenous injection of somatostatin at the time of cannulation of the papilla, and the third group received a placebo. RESULTS: Two patients in each of the somatostatin groups (1.7%) and 12 patients in the placebo group (9.8%) developed pancreatitis (P<0.05). Serum amylase levels 5 and 24 h after the procedure were lower in both groups that received somatostatin than in the placebo group (P<0.05). CONCLUSION: Somatostatin is useful in preventing post-ERCP pancreatitis. Further studies must be designed to investigate the cost-effectiveness of the drug and to determine the ideal administration route and dosage.     

Gastro-oesophageal reflux and alcoholic cirrhosis. A reappraisal

The oesophageal pH was recorded for 3 h after a test-meal in 27 healthy control subjects (group I), 40 patients with alcoholic cirrhosis (group II), and 22 patients with a normal liver and symptoms of gastro-oesophageal reflux (control refluxers). Gastro-oesophageal reflux was observed in 10 of the cirrhotic patients. Marked reflux episodes lasted longer in cirrhotic refluxers than in control refluxers (P less than 0.05). The frequency of ascites, bleeding from ruptured oesophageal varices, peripheral neuropathy and hepatic encephalopathy were not significantly different according to presence or absence of reflux. Plasma concentrations of gastrin, somatostatin, motilin and vasoactive intestinal peptide (VIP) were measured in groups I and II. Fasting plasma motilin levels, and the release of motilin and of VIP after the meal were higher in group II than in group I. Basal levels and post-prandial profiles of the four peptides tested did not differ between cirrhotics with or without gastro-oesophageal reflux. We conclude that in patients with alcoholic cirrhosis: gastro-oesophageal reflux is frequent (25%) and characterized by prolonged reflux episodes; reflux is not correlated with the degree of liver failure and plays no significant role in the rupture of oesophageal varices; and raised plasma motilin and VIP levels cannot account for the high incidence of reflux in cirrhotics.     

Acute administration of carvedilol is more effective than propranolol plus isosorbide-5-mononitrate in the reduction of portal pressure in patients with viral cirrhosis

OBJECTIVE: Propranolol is known to decrease portal pressure in cirrhotic patients with portal hypertension; however, a substantial number of patients do not respond to propranolol administration. The addition of isosorbide-5-mononitrate may enhance portal pressure reduction in patients receiving propranolol. Carvedilol is a nonselective beta-blocker with alpha(1)-adrenergic blocking activity. It has been shown to decrease portal pressure in cirrhotic patients. Additionally, carvedilol has a greater portal hypotensive effect than propranolol alone in patients with cirrhosis. The current study is aimed at comparing the acute hemodynamic effects of carvedilol with the effects of propranolol plus isosorbide-5-mononitrate in patients with viral cirrhosis. METHODS: Patients with viral cirrhosis were randomly assigned to receive an oral administration of carvedilol of 25 mg (n = 11) or an oral administration of propranolol 40 mg plus isosorbide-5-mononitrate 20 mg (n = 11). Hemodynamic values were measured at basal and 90 min after drugs administration. RESULTS: Both carvedilol and propranolol plus isosorbide-5-mononitrate significantly decreased cardiac index, heart rate, and HVPG. The magnitude of changes in HVPG observed between the basal and after drugs administration was greater in patients receiving carvedilol than in those receiving propranolol plus isosorbide-5-mononitrate (-18.6 +/- 3.6%vs-10.1 +/- 3.6%, p < 0.05). Hepatic blood flow increased following carvedilol administration but remained unchanged in patients receiving propranolol plus isosorbide-5-mononitrate. The magnitude of decrease in mean arterial pressure (MAP) did not differ between the two groups of patients. CONCLUSION: In our patients with viral cirrhosis, carvedilol is more effective than propranolol plus isosorbide-5-mononitrate in the reduction of HVPG. Carvedilol administration causes an increase in hepatic blood flow, but its systemic effects were similar to those of propranolol plus isosorbide-5-mononitrate.     

Pharmacokinetics and pharmacodynamics of organic nitrates

The pharmacokinetic and pharmacodynamic aspects of organic nitrates are discussed, with particular emphasis on the 3 major organic nitrates currently in use, nitroglycerin (NTG), isosorbide dinitrate and isosorbide-5-mononitrate. After intravenous administration, both NTG and isosorbide dinitrate exhibit large systemic clearances and both nitrates appear to be extensively distributed in vascular and other peripheral tissues. Two pharmacokinetic features appear particularly notable for NTG: there is a significant arteriovenous extraction of the drug, and its systemic clearance is related to cardiac output. Both of these features, plus other evidence, suggest that organic nitrates may be substantially removed from the systemic circulation by the vasculature itself. During nitrate tolerance, plasma drug concentrations remain elevated, but vascular activity is diminished. This apparent paradox might be explainable by a unifying hypothesis of reduced nitrate metabolism during vascular tolerance; thus, in the tolerant state, reduced systemic clearance of the intact drug brought about elevated plasma concentrations, whereas reduced cellular metabolism at the smooth muscle brought about a decrease in vascular activity. The complex relations among plasma kinetics, vascular metabolism and pharmacologic action of organic nitrates are still poorly understood.     

Hemodynamic evaluation of isosorbide dinitrate in alcoholic cirrhosis. Pharmacokinetic-hemodynamic interactions

Isosorbide dinitrate, a long-acting organic nitrate, has been shown to decrease portal pressure in the experimental animal and humans. We conducted a double-blind randomized hemodynamic evaluation of the effects of placebo and 10 mg and 20 mg isosorbide dinitrate in stable individuals with alcoholic cirrhosis. Baseline values for all three groups were similar. Isosorbide dinitrate resulted in a peak reduction of the hepatic venous gradient of 24.7% +/- 3.0%, with significantly decreased values 4 h after the administration of the 20-mg dose. A reduction of arterial pressure and cardiac index (peak decrease of 25.7% +/- 1.5%) was well tolerated by 13 of 15 patients. Changes in mean arterial pressure were not predictive of modifications in the hepatic vein wedge pressure. There was no relation between the area under the plasma isosorbide dinitrate concentration curve and hemodynamic changes. Levels of isosorbide-5-mononitrate, a vasoactive metabolite, were detectable for an 8-h period. Isosorbide dinitrate significantly reduced portal pressure in stable cirrhotics, in association with systemic hemodynamic changes. Thus, titration of isosorbide dinitrate is required to maximize hemodynamic benefits in individual patients. As the decrease in portal pressure is more predictable than the effect of previously tested pharmacologic agents, isosorbide dinitrate should be evaluated for its efficacy in the management of portal hypertension.     

Randomised double blind trial of somatostatin in the treatment of massive upper gastrointestinal haemorrhage.

In order to evaluate the effect of somatostatin in the treatment of massive upper gastrointestinal bleeding a randomised double blind trial of 95 patients has been undertaken during a 28 months period. Patients with oesophageal varices have been excluded as well as patients with diabetes. All patients were endoscoped within eight hours of admission to the hospital, whereupon the source of bleeding and types of stigmata were assessed. Forty six patients, chosen at random, were given a 72 hour infusion of somatostatin, while the remaining 49 patients received infusion of placebo. The two groups were well matched for sex, age, and source of bleeding. On the day after admission, an additional endoscopy was performed at which eight patients in the somatostatin group and 16 in the placebo group were found to have a persistent bleeding. A total of five patients in the somatostatin group and 14 in the placebo group underwent surgery (Fisher's exact test, 2-tail, p = 0.04). Rebleeding occurred in six patients in the somatostatin group, of whom five experienced rebleeding after completion of the somatostatin treatment. In the placebo group, rebleeding occurred in five patients, of whom four rebled on the day after admission. The need for blood transfusions and the mortality rate did not differ significantly between the two groups. No toxic side effects were found as a result of the infusion of somatostatin. In this study, somatostatin reduced the number of patients needing surgery with massive upper gastrointestinal bleeding.     

A prospective randomised controlled trial comparing the efficacy of somatostatin with injection sclerotherapy in the control of bleeding oesophageal varices.

Since previous reports have suggested that somatostatin may be of value in the control of acute variceal haemorrhage, we compared its efficacy with that of injection sclerotherapy in a randomised controlled clinical trial. Eighty consecutive patients with endoscopically-proven severe variceal bleeding were randomised to injection sclerotherapy (n = 41) or somatostatin (n = 39) given as a continuous infusion of 250 micrograms/h for 5 days plus daily bolus administration of 250 micrograms. The efficacy of injection sclerotherapy and somatostatin infusion in controlling haemorrhage and preventing rebleeding (censored at 5 days), mortality (censored at 28 days) and complications was compared. The aetiology of the portal hypertension and transfusion requirements was similar between the two groups, but there were more patients with severe liver disease (Child's C) in the somatostatin group. There was no significant difference between the two treatments in the initial (p = 1.0) or overall control of bleeding (p = 0.58). Furthermore, somatostatin was as effective as injection sclerotherapy in controlling bleeding in patients with severe liver disease or in those actively bleeding at the time of their endoscopy. The relative risk of rebleeding whilst receiving somatostatin compared to injection sclerotherapy was 1.39 [95% Confidence Interval (CI) 3.73; 0.52], but this was reduced to 0.98 (95% CI 0.37; 2.67) when readjusted for Child's grading, the only prognostic factor shown to be of significance. Mortality was not significantly different between the two groups of patients (p = 0.31). The relative risk of dying whilst receiving somatostatin compared to injection sclerotherapy was 1.6 (95% CI 3.93; 0.66) but was reduced to 1.03 (95% CI 0.47; 2.47) when adjusted for Child's grading, the only significant prognostic factor. Complications in the somatostatin group were minor and less frequent than after injection sclerotherapy. The results of this study indicate that somatostatin is a safe treatment, which is as effective an endoscopic injection sclerotherapy for acute variceal bleeding.     

Effect of the somatostatin analogue lanreotide on meal-stimulated portal blood flow in patients with liver cirrhosis

BACKGROUND: Lanreotide, a new long-acting somatostatin analogue, has been shown to inhibit the meal-stimulated increase of splanchnic blood flow in healthy volunteers. To date, similar data in patients with liver cirrhosis have not been available. We have examined the effect of lanreotide compared with placebo on meal-stimulated portal blood flow in patients with liver cirrhosis using Doppler ultrasound. METHODS: 20 cirrhotic patients (placebo n = 12, lanreotide n = 8) with proven portal hypertension were studied after an overnight fast. Lanreotide, at a dose of 100 microg/h, was infused intravenously over 7 h after a 1-hour basal period. In parallel to the intravenous infusion, a liquid test meal (Ensure plus, 1.5 kcal/min) was perfused for 7 h through an intraduodenal tube at a rate of 3 ml/min. Blood pressure, heart rate and portal vein blood flow (PVF, ml/min, Doppler technique) were determined at regular intervals. RESULTS: Baseline PVF amounted to 725 +/- 182 ml/min in the placebo and to 917 +/- 252 ml/min in the lanreotide group (n.s.). The meal-stimulated increase in PVF was blunted by lanreotide (AUC, % x min): 62,709.6 +/- 6,817 (placebo) vs. 45,237 +/- 2,507 (lanreotide), p < 0.05. Lanreotide also blunted the postprandial increase in heart rate for the first 2 h of meal perfusion. CONCLUSIONS: Because of potent inhibition of postprandial splanchnic hyperemia in patients with liver cirrhosis, lanreotide may be useful in the treatment of complications of portal hypertension.     

Effect of chronic treatment with nadolol plus isosorbide mononitrate on liver blood flow and liver metabolic activity in cirrhosis

OBJECTIVE: To assess the long-term effect of the addition of long-acting nitrates to beta-blockers on liver blood flow and liver metabolic activity in patients with cirrhosis and portal hypertension. METHODS: Eleven patients with cirrhosis and portal hypertension were investigated by using hepatic vein catheterization and indocyanine green (ICG) constant infusion on baseline conditions, after 1 month of treatment with nadolol, after 3 months of treatment with nadolol plus isosorbide mononitrate, and (in seven cases) after 1 year of combined treatment. RESULTS: The hepatic venous pressure gradient decreased significantly after nadolol, and more so after addition of isosorbide mononitrate. Hepatic blood flow, and ICG intrinsic hepatic clearance did not change significantly, although few cases showed an increase or decrease in either parameter. A significant correlation was found between changes in ICG intrinsic hepatic clearance and in hepatic venous pressure gradient (r = 0.62, P = 0.04). CONCLUSIONS: Liver blood flow and liver metabolic activity are not consistently affected by addition of isosorbide mononitrate to nadolol. Substantial decreases in portal pressure may be associated with a decrease in ICG intrinsic hepatic clearance.