Terlipressin is a synthetic vasopressin analog which has been recently approved in the United States by the Food and Drug Administration for the treatment of hepatorenal syndrome. Terlipressin stimulates vasopressin receptors located on the smooth muscle vasculature of the splanchnic circulation and renal tubules which results in splanchnic vasoconstriction with improved renal perfusion and antidiuretic activity, respectively.

In this review, we discuss available data regarding the FDA approved use of terlipressin, safety, and tolerability, as well as highlight alternative uses in chronic liver disease currently still under investigation.

Terlipressin is more efficacious compared to other vasoactive agents including midodrine octreotide and norepinephrine in reversal of hepatorenal syndrome and improves short-term survival. Other potential applications of terlipressin's vasoconstrictor actions reported in the literature include management of variceal hemorrhage and other complications of portal hypertension.

Approximately 40% to 95% of people with liver cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed within about one to three years after diagnosis. Several different treatments are available, including, among others, endoscopic sclerotherapy, variceal band ligation, somatostatin analogues, vasopressin analogues, and balloon tamponade. However, there is uncertainty surrounding the individual and relative benefits and harms of these treatments.

To compare the benefits and harms of different initial treatments for variceal bleeding from oesophageal varices in adults with decompensated liver cirrhosis, through a network meta-analysis; and to generate rankings of the different treatments for acute bleeding oesophageal varices, according to their benefits and harms.

We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until 17 December 2019, to identify randomised clinical trials (RCTs) in people with cirrhosis and acute bleeding from oesophageal varices.

We included only RCTs (irrespective of language, blinding, or status) in adults with cirrhosis and acutely bleeding oesophageal varices. We excluded RCTs in which participants had bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those in whom initial haemostasis was achieved before inclusion into the trial, and those who had previously undergone liver transplantation.

We performed a network meta-analysis with OpenBUGS software, using Bayesian methods, and calculated the differences in treatments using odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. We performed also the direct comparisons from RCTs using the same codes and the same technical details.

We included a total of 52 RCTs (4580 participants) in the review. Forty-eight trials (4042 participants) were included in one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those with and without a previous history of bleeding. We included outcomes assessed up to six weeks. All trials were at high risk of bias. A total of 19 interventions were compared in the trials (sclerotherapy, somatostatin analogues, vasopressin analogues, sclerotherapy plus somatostatin analogues, variceal band ligation, balloon tamponade, somatostatin analogues plus variceal band ligation, nitrates plus vasopressin analogues, no active intervention, sclerotherapy plus variceal band ligation, balloon tamponade plus sclerotherapy, balloon tamponade plus somatostatin analogues, balloon tamponade plus vasopressin analogues, variceal band ligation plus vasopressin analogues, balloon tamponade plus nitrates plus vasopressin analogues, balloon tamponade plus variceal band ligation, portocaval shunt, sclerotherapy plus transjugular intrahepatic portosystemic shunt (TIPS), and sclerotherapy plus vasopressin analogues). We have reported the effect estimates for the primary and secondary outcomes when there was evidence of differences between the interventions against the reference treatment of sclerotherapy, but reported the other results of the primary and secondary outcomes versus the reference treatment of sclerotherapy without the effect estimates when there was no evidence of differences in order to provide a concise summary of the results. Overall, 15.8% of the trial participants who received the reference treatment of sclerotherapy (chosen because this was the commonest treatment compared in the trials) died during the follow-up periods, which ranged from three days to six weeks. Based on moderate-certainty evidence, somatostatin analogues alone had higher mortality than sclerotherapy (OR 1.57, 95% CrI 1.04 to 2.41; network estimate; direct comparison: 4 trials; 353 participants) and vasopressin analogues alone had higher mortality than sclerotherapy (OR 1.70, 95% CrI 1.13 to 2.62; network estimate; direct comparison: 2 trials; 438 participants). None of the trials reported health-related quality of life. Based on low-certainty evidence, a higher proportion of people receiving balloon tamponade plus sclerotherapy had more serious adverse events than those receiving only sclerotherapy (OR 4.23, 95% CrI 1.22 to 17.80; direct estimate; 1 RCT; 60 participants). Based on moderate-certainty evidence, people receiving vasopressin analogues alone and those receiving variceal band ligation had fewer adverse events than those receiving only sclerotherapy (rate ratio 0.59, 95% CrI 0.35 to 0.96; network estimate; direct comparison: 1 RCT; 219 participants; and rate ratio 0.40, 95% CrI 0.21 to 0.74; network estimate; direct comparison: 1 RCT; 77 participants; respectively). Based on low-certainty evidence, the proportion of people who developed symptomatic rebleed was smaller in people who received sclerotherapy plus somatostatin analogues than those receiving only sclerotherapy (OR 0.21, 95% CrI 0.03 to 0.94; direct estimate; 1 RCT; 105 participants). The evidence suggests considerable uncertainty about the effect of the interventions in the remaining comparisons where sclerotherapy was the control intervention.

Based on moderate-certainty evidence, somatostatin analogues alone and vasopressin analogues alone (with supportive therapy) probably result in increased mortality, compared to endoscopic sclerotherapy. Based on moderate-certainty evidence, vasopressin analogues alone and band ligation alone probably result in fewer adverse events compared to endoscopic sclerotherapy. Based on low-certainty evidence, balloon tamponade plus sclerotherapy may result in large increases in serious adverse events compared to sclerotherapy. Based on low-certainty evidence, sclerotherapy plus somatostatin analogues may result in large decreases in symptomatic rebleed compared to sclerotherapy. In the remaining comparisons, the evidence indicates considerable uncertainty about the effects of the interventions, compared to sclerotherapy.

Vasoactive drugs form the mainstay of therapy for two of the most important complications of liver disease: hepatorenal syndrome (HRS) and acute variceal bleed (AVB). With cumulative evidence supporting the use in cirrhosis, terlipressin has been recommended for the management of HRS and AVB. However, owing to the safety concerns, terlipressin was not approved by food and drug administration (FDA) until now. In this review, we discuss the pharmacology and the major practice-changing studies on the safety and efficacy of terlipressin in patients with cirrhosis particularly focusing on existing indications like AVB and HRS and reviewing new data on the expanding indications in liver disease. The references for this review were identified from PUBMED with MeSH terms such as "terlipressin," "hepatorenal syndrome," "varices, esophagal and gastric," "ascites" and "cirrhosis." Terlipressin, a synthetic analogue of vasopressin, was introduced in 1975 to overcome the adverse effects of vasopressin. Terlipressin is an effective drug for HRS reversal in patients with liver cirrhosis and acute-on-chronic liver failure. There is documented mortality benefit with terlipressin therapy in HRS and AVB. Adverse effects are common with terlipressin and need to be monitored strictly. There is some evidence to support the use of this drug in refractory ascites, hepatic hydrothorax, paracentesis-induced circulatory dysfunction and perioperatively during liver transplantation. However, terlipressin is not yet recommended for such indications. In conclusion, terlipressin has stood the test of time with expanding indications and clear prerequisites for clinical use. Our review warrants a fresh perspective on the efficacy and safety of terlipressin.

We aimed to compare the efficacy of different drugs facilitating endoscopy in patients with acute variceal bleeding.

Databases were searched to identify randomized controlled trials which compared the efficacy of vasoactive drugs (vasopressin, terlipressin, octreotide, somatostatin) with placebo or each other. The primary outcomes were 6-week and 5-day mortality. Secondary outcomes were 5-day rebleeding, control of initial bleeding and adverse events. Pairwise and network meta-analysis were performed.

We identified 14 RCTs involved 2,187 patients. Four drugs had comparable clinical efficacy in all involving outcomes, except for adverse events. However, we do exhibit a superiority when vasopressin (OR, 4.40; 95% CI: 1.04-19.57), terlipressin (OR, 4.58; 95% CI: 1.63-13.63), octreotide (OR, 5.79; 95% CI: 2.41-16.71) and somatostatin (OR, 5.15; 95% CI: 1.40-27.39) were compared to placebo respectively as for initial hemostasis. In addition, only octreotide was more effective than placebo in decreasing 5-day rebleeding (OR, 0.44; 95% CI: 0.22-0.90). Meanwhile, octreotide was shown to have the highest probability ranking the best to improve initial hemostasis (mean rank =1.8) and carries a lowest risk of adverse events (9.1%) and serious adverse events (0.0%) compared to other drugs.

Balanced with curative effect and tolerability, octreotide may be the preferred vasoactive drug facilitating endoscopy.

Our purpose was to conduct a meta-analysis to compare the effectiveness of vasopressin/terlipressin and somatostatin/octreotide on variceal re-bleeding within and after 5 days of initial control bleeding.

A search was conducted of PubMed, the Cochrane database, and Google Scholar until June 31, 2014 using combinations of the search terms: esophageal varices, variceal re-bleeding, recurrent variceal hemorrhage, early re-bleeding, vasopressin, somatostatin, terlipressin, octreotide. Inclusion criteria were: (1) randomized controlled trials, (2) patients with esophageal or esophageal and gastric varices confirmed by endoscopy, (3) re-bleeding control was evaluated, (4) treatment with somatostatin/vasopressin. Outcome measures were the re-bleeding rates within 5 days (≤ 5 days) or after 5 days (>5 days) after initial treatment.

Six studies were included in the analysis. Five studies had complete data of re-bleeding rate within 5 days after initial treatment, and the combined odds ratio (OR) of 0.87 [95% confidence interval (CI) 0.51, 1.50] indicated that there was no difference in the re-bleeding rate between patients treated with vasopressin/terlipressin or somatostatin/octreotide. Two studies had complete data of the re-bleeding rate 5 days after initial treatment, and the combined OR of 1.12 (95% CI 0.64, 1.95) indicated there was no difference in the re-bleeding rate between patients who were treated with vasopressin/terlipressin or somatostatin/octreotide.

There is no difference between vasopressin/terlipressin and somatostatin/octreotide in prevention of re-bleeding after the initial treatment of bleeding esophageal varices.

The upper gastrointestinal bleeding remains the most frequent emergency in gastroenterology. Due to the different therapeutic approach a distinction between the variceal and the non-variceal bleeding has been established. A risk assessment for the individual patient is crucial for timing of the endoscopic procedure as well as for the estimation of prognosis. This review gives an overview on modern therapeutic techniques for both, variceal and non-variceal bleeding highlighting on success rates but also on potential complications of the different therapeutic interventions.

The management of variceal bleeding remains a clinical challenge with a high mortality. Standardisation in supportive and new therapeutic treatments seems to have improved survival within the last 25 years. Although overall survival has improved in recent years, mortality is still closely related to failure to control initial bleeding or early re-bleeding occurring in up to 30-40% of patients. Initial procedures are to secure and protect the airway, and administer volume replacement to stabilize the patient. Treatment with vasoactive drugs should be started as soon as possible, since a reduction in portal pressure is associated with a better control of bleeding and may facilitate later endoscopic procedures. Vasopressin and its analogues Terlipressin and somatostatin and analogues are the two types of medicine, which has been evaluated. In meta-analysis, only Terlipressin have demonstrated effects on control of bleeding and on mortality. Somatostatin and its analogues improve control of bleeding, but show in meta-analysis no effects on mortality. Approximately 20% of patients with variceal bleeding will suffer from an infection, when they are hospitalized. Invasive procedures will further increase the risk of bacterial infections. Meta-analysis of clinical trials comparing antibiotics with placebo demonstrates that antibiotic prophylaxis improves survival with 9% (p<0.004). Quinolones or intravenous cephalosporins should be preferred. Early endoscopy should be performed in patients with major bleeding. Endoscopic therapy increases control of bleeding and decreases the risks of rebleeding and mortality. Ligation is probably more effective than sclerotherapy with fewer complications and should therefore be preferred, if possible. In case of gastric variceal bleeding, tissue adhesives should be used.

Improvements in resuscitation and prevention of complications have together with introduction of vasoactive drugs and refinement of endoscopic therapy majorily changed the prognosis of the patient presenting with variceal bleeding.

Emergency endoscopy plays the most important role in diagnosis and treatment of patients with esophageal variceal bleeding. Endoscopic sclerotherapy (EST), placement of esophageal band ligatures (EVL), medicamentous treatment using somatostatin and its derivatives and balloon tamponade are the methods most frequently applied in treatment of the bleeding esophageal varices.

Endoscopic reports on the patients with bleeding esophageal and gastric varices were retrospectively analyzed in the emergency unit of the Clinic of Gastroenterology and Hepatology, Clinical Center of Serbia over the five-year period--since January 2001 till December 2005.

The total of approximately 3, 954 emergency upper endoscopies were performed due to the upper gastrointestinal tract bleeding. Out of the total number of patients, bleeding was diagnosed in 324 (8.2%) patients due to the esophageal varices. In the group of patients with bleeding esophageal varices, the total of 252 (77.8%) males and 72 (22.2%) females averagely aged 56.8 + 7.5 years (range 24 - 80 years) were examined. The primary sclerosant therapy with absolute alcohol was applied in 118 (36.4%) patients, while Blakemore probe tamponade was performed in 145 (44.8%) patients with bleeding esophageal varices. The total of 240 (74.1%) patientswere treated with vasoactive substances (somatostatin and its analogues), as additional therapy and control of the primary hemostasis. It was evidenced that out of 118 patients intra and paravariceally treated with the sclerosant agent (absolute alcohol) hemostasis was achieved in 47 (39.8%). Out of 145 patients subjected to Blakemore probe placement, bleeding was successfully arrested in 117 (80.7%) patients. Somatostatin and its analogues as primary and only treatment of the bleeding esophageal varices were applied in 71 (29.6%) patients, while in the remaining 169 (70.4%) patients, they were applied as additional therapy to the endoscopic sclerotherapy and mechanical treatment of bleeding. Out of 71 patients treated with somatostatin preparations as the only therapeutic option, 45 (63.4%) responded positively by arrest of bleeding for 72 hours.

Treatment of the acute bleeding esophageal varices is focused on the arrest of bleeding, prevention of early recurrent bleeding and reduction of mortality. Based on the most recent studies, efficacy of the modern endoscopic therapy in the form of sclerotherapy and band ligature placement, as well as application of vasoactive substances reaches up to 90%. Our results evidence minimal efficacy of the sclerotherapy (approximately 40%), which indicates the need of better preparation of patients for the intervention itself and additional education of the personnel.

Somatostatin and its analogues have been compared with a variety of other treatments for the treatment of variceal bleeding in cirrhotic patients. Meta-analyses of studies comparing somatostatin or octreotide with vasopressin or terlipressin have shown that somatostatin is somewhat superior to vasopressin and equivalent to terlipressin in controlling bleeding and has significantly fewer side effects; no difference in mortality was observed. Octreotide was somewhat better than vasopressin and terlipressin in controlling bleeding, with similar mortality. Meta-analysis of trials comparing somatostatin or octreotide with endoscopic sclerotherapy shows that both drugs are equivalent to sclerotherapy for bleeding control, early rebleeding and survival. Complications are much less frequent with drug treatment. Nine trials have compared endoscopic therapy with therapeutic regimens combining endoscopic treatment with somatostatin, octreotide or vapreotide. Meta-analysis show that the combined regimens increase the 5 days bleeding control rate of endoscopic treatments by over 20%, although there is no difference in mortality. Comparisons of somatostatin and octreotide with combined regimens of sclerotherapy + somatostatin and sclerotherapy + octreotide have shown that the combined regimens were better than drug treatments alone in controlling bleeding and preventing early rebleeding, while complications were significantly less frequent with drug therapy.

Variceal haemorrhage is a common medical emergency with a high mortality (30-50%). Adequate resuscitation is vital, and once stabilised the patient should be moved to a high-dependency area. Antibiotics reduce mortality, and the vasoactive drug terlipressin should be administered if early endoscopy is unavailable. Early endoscopy is essential both to make the diagnosis and to allow therapeutic measures to be performed. The evidence suggests that variceal band ligation is the most effective therapy for oesophageal varices. If gastric varices are found at the index endoscopy the evidence at present is inadequate to be certain which is the best treatment, but both endoscopic therapy with cyanoacrylate or thrombin and transjugular intrahepatic portosystemic stent shunt (TIPSS) have been reported to be of benefit. When initial treatments fail, rescue therapy should be initiated. Most authorities agree that TIPSS is the rescue therapy of choice. Many questions remain concerning the treatment of acute variceal bleeding, particularly the ideal therapy for gastric varices and the role of combination vasoactive and endoscopic therapy. Randomised controlled trials are required to answer these important issues.

Endoscopy has become the first and primary diagnostic and therapeutic modality in the management of patients with severe gastrointestinal bleeding. Panendoscopy, push enteroscopy, and colonoscopy provide the diagnostic, prognostic, and therapeutic elements to improve patient outcomes and to reduce morbidity and mortality from severe GI hemorrhage. Recent improvements in endoscopic hemostatic techniques and in imaging modalities using wireless capsule endoscopy suggest that diagnostic and therapeutic endoscopy will be even more important in determining patient outcomes in the future.

The dose of somatostatin used for variceal bleeding (250 microg/h) is lower than that proven to effectively decrease portal pressure and azygos blood flow (500 microg/h). Moreover, i.v. somatostatin boluses have greater effects than continuous infusions. The aim of this study was to investigate whether higher doses of somatostatin and repeated boluses may increase its efficacy in controlling variceal bleeding.

A total of 174 patients with acute variceal bleeding were randomized to receive for 48 h: (A) one 250 microg bolus +250 microg/h infusion; (B) three 250 microg boluses +250 microg/h infusion; (C) three 250 microg boluses +500 microg/h infusion.

The three schedules of somatostatin were equally effective in controlling variceal bleeding (73, 75 and 81%, respectively, NS). Multivariate analysis showed active bleeding at endoscopy (n=75) as the only predictor of failure to control bleeding. In these patients, the 500 microg/h infusion dose achieved a higher rate of control of bleeding (82 vs. 60%, P<0.05), less transfusions (3.7 +/- 2.7 vs. 2.5 +/- 2.3 UU, P=0.07) and better survival (93 vs. 70%, P<0.05) than schedules A/B.

Somatostatin is highly effective in controlling variceal bleeding. Patients with active bleeding at emergency endoscopy may benefit from higher doses of somatostatin infusion.

Each variceal bleed is associated with 20% to 30% risk of dying. Management of portal hypertension after a bleed consists of (1) control of bleeding and (2) prevention of rebleeding. Effective control of bleeding can be achieved either pharmacologically by administering somatostatin or octreotide or endoscopically via sclerotherapy or variceal band ligation. In practice, both pharmacologic and endoscopic therapy are used concomitantly. Rebleeding can be prevented by endoscopic obliteration of varices. In this setting, variceal ligation is the preferred endoscopic modality. B-blockade is as effective as endoscopic therapy and, in combination, the two modalities may be additive.

Many advances in the management of portal hypertension and variceal hemorrhage have occurred during the last 10 years. Effective therapy for primary prevention of variceal hemorrhage is now available in the form of nonselective beta-blockers. Active bleeding should be managed with terlipressin, somatostatin or its analogues, and endoscopic therapy; TIPS and surgery are reserved as salvage therapy for patients who fail endoscopic treatment. Survivors of a variceal hemorrhage should be evaluated for liver transplantation. Specific treatment may be provided with EVL while these patients await transplantation. Patients who fail endoscopic treatment may be treated by TIPS or surgery.

Endoscopic therapy and in particular endoscopic variceal banding ligation, in experienced hands, is the treatment of choice for acute variceal bleeding which remains a major cause of death in patients with cirrhosis and portal hypertension. Pharmacological therapy with Glypressin or somatostatin can be useful to gain time when the endoscopic expertise is not available or to help to obtain a clearer endoscopic view. Transjugular intrahepatic porto-systemic stent shunt is currently used for endoscopic failures, producing similar results with the surgical portacaval shunts. Which one of the two should be preferred, since they both work best in relatively compensated patients, should be a balance between the available surgical and radiological expertise, the urgency of the situation and the expected course of the disease.

Terlipressin (triglycyl lysine vasopressin) is a synthetic analogue of vasopressin, which has been used in the treatment of acute variceal hemorrhage. In contrast to vasopressin, terlipressin can be administered as intermittent injections instead of continuous intravenous infusion and it has a safer adverse reactions profile. However, its effectiveness remains uncertain.

To determine if treatment with terlipressin improves outcome in acute esophageal variceal hemorrhage and is safe.

Randomized clinical trials were identified by searching the following databases: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, the Cochrane Hepato-Biliary Group Controlled Trials Register, Biosis, and Current Contents. The bibliographies of identified publications were checked. Experts in the field and the manufacturers of terlipressin were contacted.

All randomized clinical trials which compared terlipressin with: (a) placebo or no treatment, (b) balloon tamponade, (c) endoscopic treatment, (d) octreotide, (e) somatostatin and (f) vasopressin, in the setting of acute variceal hemorrhage.

Eligibility, trial quality assessment and data extraction were done independently by two reviewers. The primary outcome measure was mortality. Secondary outcomes were failure of initial hemostasis, rebleeding, procedures required for uncontrolled bleeding or rebleeding, transfusion requirements and length of hospitalization.

Twenty studies were identified for all the comparison groups, involving 1609 patients. There were seven studies (with 443 patients) comparing terlipressin to placebo, five of which were considered to be high quality studies based on the Jadad scale. The meta-analysis indicates that terlipressin was associated with a statistically significant reduction in all cause mortality compared to placebo (relative risk 0.66, 95% confidence interval 0.49 to 0.88). Three studies (with 302 patients) were identified comparing terlipressin to somatostatin, two of which were high quality studies; only one high quality study (219 patients) comparing terlipressin to endoscopic treatment was identified. Within the limited power provided by these small numbers of patients, no statistically significant difference was demonstrated between terlipressin and either somatostatin or endoscopic treatment in any of the outcomes. For the remaining comparison groups (terlipressin versus balloon tamponade, terlipressin versus octreotide and terlipressin versus vasopressin) only small, low quality studies were identified and no difference was demonstrated in any of the major outcomes. There was no difference between the terlipressin group and any of the comparison groups in the number of adverse events that caused death or withdrawal of medication.

On the basis of a 34% relative risk reduction in mortality, terlipressin should be considered to be effective in the treatment of acute variceal hemorrhage. Further, since no other vasoactive agent has been shown to reduce mortality in single studies or meta-analyses, terlipressin might be the vasoactive agent of choice in acute variceal bleeding.

The aim of this study was to compare the efficacy of somatostatin versus endoscopic sclerotherapy in the management of digestive bleeding caused by rupture of esophageal varices. Forty patients were evaluated; 21 were randomly assigned to receive somatostatin (initial 250 micrograms followed by a 48-hour continuous infusion of 250 micrograms/h and 250 micrograms 6/6 h bolus in the first 24 hours) and 19 to receive endoscopic sclerotherapy with ethanolamine oleate 5%. The patients were evaluated after 48 hours and after 7 days of treatment. Both groups of patients were similar in sex, age, gravity of the hemorrhage and liver dysfunction. Therapeutic failure occurred in 26.3% and 35.7% in the group of endoscopic sclerotherapy (48 h and 7 days respectively), and in 23.8% and 21.4% in the group of somatostatin. The need of blood transfusion (3.38 U in the group of endoscopic sclerotherapy and 2.42 U in the group of somatostatin) and the mortality rate (31.6% in the group of endoscopic sclerotherapy and 28.6% in the group of somatostatin) were also similar (P > 0.05). The authors conclude that somatostatin is as effective as endoscopic sclerotherapy and that it should be considered in the treatment of acute esophageal variceal bleeding.

The last half century has witnessed great advances in the understanding of the pathogenesis and natural history of portal hypertension in cirrhotics. Several pharmacologic and endoscopic techniques have been developed for the treatment of portal hypertension. The use of these agents in a given patient must be based on an understanding of the stage in the natural history of the disease and the relative efficacy and safety of the available treatment options.

Terlipressin decreases portal pressure. However, its effects on variceal pressure have been poorly investigated. This study investigated the variceal, splanchnic and systemic hemodynamic effects of terlipressin.

Twenty cirrhotic patients with esophageal varices grade II-III, and portal pressure > or =12 mmHg were studied. Hepatic venous pressure gradient, variceal pressure and systemic hemodynamic parameters were obtained. After baseline measurements, in a double-blind administration, 14 patients received a 2mg/iv injection of terlipressin and six patients received placebo. The same measurements were repeated 60 min later.

No demographic or biochemical differences were observed in basal condition between groups. Terlipressin produced significant decreases in intravariceal pressure from 20.9+4.9 to 16.3+/-4.7 mmHg (p<0.01, -21+/- 16%), variceal pressure gradient from 18.9+/-4.8 to 13.5+/-6.0 mmHg (p<0.01, -28+/-27%), estimated variceal wall tension from 78+/-29 to 59+/-31 mmHg x mm (p<0.01, -27+/-22%), and hepatic venous pressure gradient from 19.4+/-4.5 to 16.8+/-5 mmHg (p<0.01, -14+/-12%) at 60 min. The change in variceal pressure after 60 min of terlipressin administration was greater than the change in wedge hepatic venous pressure (-4.7 mmHg vs -0.5 mmHg, respectively, p<0.0001). Terlipressin also caused significant decreases in heart rate and cardiac index and increases in mean arterial pressure and peripheral vascular resistance.

Our results demonstrate that terlipressin produces significant and prolonged decreases in variceal pressure and variceal wall tension and has intrinsic effects on portal pressure and systemic hemodynamics. Variceal pressure provides a better assessment of the effects of terlipressin administration on esophageal varices than hepatic venous pressure gradient.

Recent trials have shown that somatostatin (SMT) is as effective as sclerotherapy in the treatment of acute variceal bleeding and that the combination of both treatments is more effective than sclerotherapy alone. To assess whether the addition of sclerotherapy improves the efficacy of SMT alone, all patients admitted to our unit with gastrointestinal bleeding and with suspected cirrhosis received a continuous infusion of SMT (250 micrograms/h). Endoscopy was performed between 1 and 5 hours later, and patients with esophageal variceal bleeding were randomized to receive or not to receive sclerotherapy. In both groups, SMT infusion was continued for 5 days. Fifty patient admissions were allocated to each group. Therapeutic failure occurred in 21 cases of the SMT group and in 7 cases of the combined-therapy group (P =.002). Failure to control the acute episode occurred in 24% vs. 8% (P =.03) and early rebleeding in 24% vs. 7% (P =.03), respectively. Transfusional requirements were significantly higher in the SMT group, while the incidence of complications was lower (8% vs. 24%; P =.029). In the multivariate analysis, the presence of shock at admission and active bleeding during endoscopy were the variables that better predicted the failure of therapy with SMT alone. Mortality at 6 weeks was similar. These data demonstrate that the addition of sclerotherapy significantly improves the efficacy of SMT alone for the treatment of acute variceal bleeding, although it also increases the rate of complications. Patients with shock and those with active bleeding are more likely to benefit from this combined therapy.

The type of emergency treatment administered to patients with suspected variceal bleeding is important, as the episode is associated with a high mortality rate. Moreover, rebleeding is common during the first few days after the initial haemorrhage. Several techniques are available to control variceal haemorrhage including pharmacotherapy (vasopressin, terlipressin, somatostatin and octreotide), balloon tamponade, endoscopic techniques, transjugular intrahepatic portosystemic shunt and shunt surgery. The majority of these require specialized equipment and/or experienced personnel, which are not always available in every hospital. In such situations, pharmacotherapy represents the most practical method of establishing haemodynamic control prior to the administration of definitive treatment. Pharmacotherapy can be initiated immediately upon admission to stabilize the patient prior to diagnostic endoscopy, which subsequently improves the efficacy and ease of administration of further endoscopic intervention. The optimal pharmacological agent should be both effective and safe. A drug with no side effects will not complicate the management of critical patients and can be administered over an extended period to reduce the incidence of rebleeding and improve prognosis. Meta-analysis of clinical studies has revealed that of the vasoactive drugs available somatostatin is effective with significantly fewer side effects and currently appears to represent the best choice for treatment. The available evidence suggests that the early administration of pharmacotherapy, as part of a specific treatment regimen, offers significant benefit to patients with variceal bleeding and its administration optimizes emergency care.

Variceal haemorrhage is the most serious complication of portal hypertension and is associated with a high mortality rate. The first stage of treatment is to stabilize the patient, followed by emergency diagnostic endoscopy to identify the source of the bleeding. If active variceal bleeding is found, endoscopic intervention is performed to induce haemostasis. The endoscopic techniques commonly used to treat bleeding gastro-oesophageal varices include injection sclerotherapy and band ligation. Sclerotherapy achieves haemostasis through the induction of thrombosis or by external compression of the vessel and should be performed during diagnostic endoscopy. Band ligation achieves haemostasis by physical constriction of the varix. Band ligation may be less effective than sclerotherapy in the treatment of actively bleeding oesophageal varices and is therefore recommended for subsequent elective treatment of non-bleeding varices. However, such techniques are difficult to perform during active bleeding. This has prompted the search for improved treatment protocols. Vasoactive drugs which lower portal hypertension have been administered before, during and after endoscopy and may offer an improvement in treatment. Data from several trials have suggested that pharmacotherapy in combination with endoscopic intervention is more effective than endoscopic treatment alone. Furthermore, pharmacotherapy continued for 5 days following endoscopy significantly reduces the incidence of variceal rebleeding. A strict regimen for emergency endoscopy should be used with sclerotherapy forming the basis of treatment--administered in combination with pharmacotherapy, to optimize clinical outcome. However, there is still debate concerning what is the most effective drug for treating variceal haemorrhage.

Recent advances in the pharmacology of portal hypertension are reviewed, against the background of existing knowledge and current clinical research. The most recent trials are analysed, and conclusions made about the use of drugs in acute variceal haemorrhage, as well as directions for further clinical trials and research.

Terlipressin is a long-acting vasopressin analogue that has been proved useful in the treatment of variceal haemorrhage. This study investigates the time profile of the haemodynamic effects of terlipressin on portal hypertension as well as the efficacy in decreasing portal-pressure and collateral blood flow of reduced doses, suitable for longer therapy to prevent early rebleeding.

Splanchnic and systemic haemodynamics were measured in 23 patients with cirrhosis and portal hypertension in baseline conditions and at 30 min, 1, 2, 3 and/or 4 h after the double-blind administration of a single intravenous injection of 1 mg (n=8) or 2 mg (n=8) of terlipressin, or placebo (n=7).

Placebo caused no significant effects. At 30 min of terlipressin administration, the hepatic venous pressure gradient (1 mg: -16+/-9%, 2 mg: -21+/-11%; p<0.01) and azygos blood flow (1 mg: -19+/-13%, 2 mg: -25+/-17%; p<0.05) were significantly reduced. These effects were still significant at 4 h (2 mg) or 3 h (1 mg). Both doses moderately increased arterial pressure at 1 h. At 4 h, neither arterial pressure nor peripheral vascular resistance was significantly modified by either dose of terlipressin. Terlipressin caused no significant changes in hepatic blood flow.

In patients with cirrhosis, a single injection of 2 mg of terlipressin significantly and markedly reduces portal pressure and azygos blood flow for up to 4 h. The effects of a reduced dose (1 mg) were almost as pronounced and prolonged, suggesting that after the initial control of variceal bleeding, terlipressin therapy could be maintained for several days at low dosage to reduce the risk of early rebleeding.

In the last decade, endoscopic haemostasis, including injection sclerotherapy and variceal ligation has become the standard method for the treatment of variceal haemorrhage. While the use of vasopressin has been hampered by severe side effects, the development of new vasoactive agents such as terlipressin, somatostatin and octreotide has opened new indications for these pharmacological therapies. These agents are effective, safe and easy to use. They could be recommended as stop-gap treatment before endoscopy can be arranged. They can also be used as adjunct therapy for endoscopic haemostasis in acute variceal haemorrhage.

This article reviews the management of severe upper gastrointestinal bleeding in the patient with chronic liver diseases. The initial assessment, diagnostic work-up, and treatment options for variceal and nonvariceal bleeding are discussed. The role of diagnostic and therapeutic endoscopy for esophagogastric varices is reviewed with special emphasis on new endoscopic techniques including variceal band ligation and cyanoacrylate injection. Various pharmacologic, surgical, and radiologic treatment options for variceal bleeding also are discussed. In addition, nonvariceal causes of severe upper gastrointestinal bleeding are reviewed including peptic ulcer diseases, Mallory-Weiss tear, portal hypertensive gastropathy, and gastric antral vascular ectasia.

Between 1988 and 1990 an unblinded, randomized trial of terlipressin or vasopressin plus transdermal nitroglycerin, as part of a treatment strategy including emergency sclerotherapy for actively bleeding varices, was conducted during 165 admissions in 137 patients with cirrhosis and upper digestive bleeding. Eighty-four patient admissions were assigned to terlipressin (2 mg every 6 h) and 81 to vasopressin (0.4 to 0.8 unit per min) plus transdermal nitroglycerin (20 to 80 mg). The two groups were comparable for relevant clinical data, but there were slightly more patients with hepatocellular carcinoma or terminal conditions in the terlipressin group. After the 24-h study period, failure to control bleeding was 20/84 (25%) in the vasopressin and 14/81 (17%) in the terlipressin group (p = 0.19). Corresponding figures for patients bleeding from varices (emergency sclerotherapy in 43 and 45, respectively) were 13/55 (24%) and 5/56 (9%; p = 0.035), from other sources 5/16 (31%) and 2/15 (13%; p = 0.23), from undefined sources 2/10 (20%) and 7/13 (54%; p = 0.1). In a logistic multivariate regression model the odds ratio for terlipressin adjusted for prognostic factors was 0.45 (p = 0.07). There were seven major side effects requiring treatment discontinuation in the vasopressin and one in the terlipressin group. These results suggest that terlipressin alone is as effective as vasopressin plus transdermal nitroglycerin, with less severe side effects, in 24-h control of upper gastrointestinal bleeding in patients with cirrhosis.

Gastric mucosal perfusion is increased in portal-hypertensive gastropathy, and this may contribute to gastric bleeding from these lesions. Therefore drugs reducing gastric mucosal perfusion may be beneficial in the treatment of overt bleeding from portal-hypertensive gastropathy. In this study gastric mucosal perfusion was assessed in 28 cirrhotic patients with portal-hypertensive gastropathy under basal conditions and after double-blind intravenous administration of vasopressin (0.4 U/min), glypressin (2-mg injection) or placebo, with laser-Doppler flowmetry and reflectance spectrophotometry. Vasopressin and glypressin induced a significant increase in blood pressure and a decrease in heart rate. These effects were more pronounced in the vasopressin group. Both vasopressin and glypressin induced a sustained and similar reduction in gastric mucosal perfusion as assessed by laser-Doppler flowmetry (-36% +/- 8% and -34% +/- 6%, respectively; p < 0.05 with respect to basal values and with respect to the control group), whereas placebo had no effect. Both drugs significantly reduced the oxygen content of the gastric mucosa; however, the impairment in mucosal oxygenation was greater (p < 0.05) in the vasopressin group (-17% +/- 3%) than in the glypressin group (-6% +/- 0.1%). We conclude that the increased gastric perfusion in cirrhotic patients with portal-hypertensive gastropathy may be reduced by either vasopressin or glypressin. These findings support the use of these drugs in clinical trials treating bleeding portal-hypertensive gastropathy. The lower reduction in gastric mucosal oxygen content observed with glypressin could decrease the incidence of ischemic adverse events associated with the use of vasopressin.