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Roberts D, Best LM, Freeman SC, Sutton AJ, Cooper NJ, Arunan S, Begum T, Williams NR, Walshaw D, Milne EJ, Tapp M, Csenar M, Pavlov CS, Davidson BR, Tsochatzis E, Gurusamy KS. Treatment for bleeding oesophageal varices in people with decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2021; 4:CD013155. [PMID: 33837526 PMCID: PMC8094233 DOI: 10.1002/14651858.cd013155.pub2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND 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. OBJECTIVES 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. SEARCH METHODS 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. SELECTION CRITERIA 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. DATA COLLECTION AND ANALYSIS 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. MAIN RESULTS 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. AUTHORS' CONCLUSIONS 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.
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Affiliation(s)
- Danielle Roberts
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Lawrence Mj Best
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Suzanne C Freeman
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Alex J Sutton
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Nicola J Cooper
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Sivapatham Arunan
- General and Colorectal Surgery, Ealing Hospital and Imperial College, London, Northwood, UK
| | | | - Norman R Williams
- Surgical & Interventional Trials Unit (SITU), UCL Division of Surgery & Interventional Science, London, UK
| | - Dana Walshaw
- Acute Medicine, Barts and The London NHS Trust, London, UK
| | | | | | - Mario Csenar
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Chavdar S Pavlov
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Brian R Davidson
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Emmanuel Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Kurinchi Selvan Gurusamy
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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Abstract
Cirrhosis is the fifth leading cause of death in adults. Advanced cirrhosis can cause significant portal hypertension (PH), which is responsible for many of the complications observed in patients with cirrhosis, such as varices. If portal pressure exceeds a certain threshold, the patient is at risk of developing life-threatening bleeding from varices. Variceal bleeding has a high incidence among patients with liver cirrhosis and carries a high risk of mortality and morbidity. The management of variceal bleeding is complex, often requiring a multidisciplinary approach involving pharmacological, endoscopic, and radiologic interventions. In terms of management, three stages can be considered: primary prophylaxis, active bleeding, and secondary prophylaxis. The main goal of primary and secondary prophylaxis is to prevent variceal bleeding. However, active variceal bleeding is a medical emergency that requires swift intervention to stop the bleeding and achieve durable hemostasis. We describe the pathophysiology of cirrhosis and PH to contextualize the formation of gastric and esophageal varices. We also discuss the currently available treatments and compare how they fare in each stage of clinical management, with a special focus on drugs that can prevent bleeding or assist in achieving hemostasis.
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Zou Z, Yan X, Lu H, Qi X, Gu Y, Li X, Wu B, Qi X. Comparison of drugs facilitating endoscopy for patients with acute variceal bleeding: a systematic review and network meta-analysis. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:717. [PMID: 32042733 PMCID: PMC6989971 DOI: 10.21037/atm.2019.12.26] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND We aimed to compare the efficacy of different drugs facilitating endoscopy in patients with acute variceal bleeding. METHODS 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. RESULTS 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. CONCLUSIONS Balanced with curative effect and tolerability, octreotide may be the preferred vasoactive drug facilitating endoscopy.
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Affiliation(s)
- Ziyuan Zou
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
- The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xinwen Yan
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
- The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Huanpeng Lu
- The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xingshun Qi
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang 110840, China
| | - Ye Gu
- Department of Gastroenterology, The Sixth Peoples Hospital of Shenyang, Shenyang 110003, China
| | - Xun Li
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China
| | - Xiaolong Qi
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
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Zhou X, Tripathi D, Song T, Shao L, Han B, Zhu J, Han D, Liu F, Qi X. Terlipressin for the treatment of acute variceal bleeding: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2018; 97:e13437. [PMID: 30508958 PMCID: PMC6283114 DOI: 10.1097/md.0000000000013437] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIM Acute variceal bleeding (AVB) is life-threatening. We aimed to systematically review the current evidence regarding the efficacy and safety of terlipressin for AVB in liver cirrhosis. METHODS We searched the PubMed, EMBASE, and Cochrane Library databases. The reference list was also hand-searched. Using a random-effect model, we combined the data obtained according to the different time points when the events developed. Odds ratio (OR) and weighted mean difference (WMD) were calculated. Quality of evidence was evaluated by the GRADE methodology. RESULTS Thirty randomized controlled trials with 3344 patients were included. Compared with no vasoactive drug, terlipressin significantly improved the control of bleeding within 48 hours (OR = 2.94, P = .0008) and decreased the in-hospital mortality (OR = 0.31, P = .008). Compared with somatostatin, terlipressin had a significantly higher risk of complications (OR = 2.44, P = .04). Compared with octreotide, terlipressin had a significantly inferior control of bleeding within 24 hours (OR = 0.37, P = .007). Compared with vasopressin, terlipressin had a significantly lower risk of complications (OR = 0.15, P = .02). Compared with terlipressin combined with endoscopic variceal ligation, terlipressin alone had significantly higher 5-day treatment failure (OR = 14.46, P = .01) and transfusion requirements within 49 to 120 hours (WMD = 1.20, P = .002). No outcome was significantly different between terlipressin and sclerotherapy. Compared with balloon tamponade, terlipressin significantly decreased the 30-day rebleeding (OR = 0.05, P = .001) and transfusion requirements (WMD = -2.70, P = .02). Quality of evidence was very low to moderate. CONCLUSION Our findings were in accordance with the current recommendations regarding terlipressin for the treatment of AVB in cirrhosis. However, due to low quality of evidence, further studies are recommended.
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Affiliation(s)
- Xinmiao Zhou
- Meta-Analysis Interest Group & Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area
- Postgraduate College, Jinzhou Medical University, Jinzhou
- Department of Gastroenterology, No. 463 Hospital of Chinese PLA
| | - Dhiraj Tripathi
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Tingxue Song
- Meta-Analysis Interest Group & Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area
- Department of Gastroenterology, No. 463 Hospital of Chinese PLA
| | - Lichun Shao
- Department of Gastroenterology, No. 463 Hospital of Chinese PLA
| | - Bing Han
- Meta-Analysis Interest Group & Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area
- Postgraduate College, Jinzhou Medical University, Jinzhou
| | - Jia Zhu
- Meta-Analysis Interest Group & Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area
- Postgraduate College, Shenyang Pharmaceutical University, Shenyang, P.R. China
| | - Dan Han
- Meta-Analysis Interest Group & Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area
| | - Fufang Liu
- Meta-Analysis Interest Group & Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area
- Postgraduate College, Jinzhou Medical University, Jinzhou
| | - Xingshun Qi
- Meta-Analysis Interest Group & Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area
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Wang C, Han J, Xiao L, Jin CE, Li DJ, Yang Z. Efficacy of vasopressin/terlipressin and somatostatin/octreotide for the prevention of early variceal rebleeding after the initial control of bleeding: a systematic review and meta-analysis. Hepatol Int 2014; 9:120-9. [PMID: 25788386 DOI: 10.1007/s12072-014-9594-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/23/2014] [Accepted: 11/10/2014] [Indexed: 01/10/2023]
Abstract
PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSION There is no difference between vasopressin/terlipressin and somatostatin/octreotide in prevention of re-bleeding after the initial treatment of bleeding esophageal varices.
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Affiliation(s)
- Chao Wang
- Department of General Surgery, Tongji Hospital, Tongji Medical College, Science and Technology of Huazhong University, No. 1095 Liberation Avenue, Wuhan, 430030, China,
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Stefaniotou A, Varvarousi G, Varvarousis DP, Xanthos T. The effects of nitroglycerin during cardiopulmonary resuscitation. Eur J Pharmacol 2014; 734:42-9. [PMID: 24726850 DOI: 10.1016/j.ejphar.2014.04.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/15/2014] [Revised: 04/03/2014] [Accepted: 04/03/2014] [Indexed: 12/31/2022]
Abstract
The outcome for both in-hospital and out-of hospital cardiac arrest remains dismal. Vasopressors are used to increase coronary perfusion pressure and thus facilitate return of spontaneous circulation during cardiopulmonary resuscitation. However, they are associated with a number of potential adverse effects and may decrease endocardial and cerebral organ blood flow. Nitroglycerin has a favourable haemodynamic profile which promotes forward blood flow. Several studies suggest that combined use of nitroglycerin with vasopressors during resuscitation, is associated with increased rates of resuscitation and improved post-resuscitation outcome. This article reviews the effects of nitroglycerin during cardiopulmonary resuscitation and postresuscitation period, as well as the beneficial outcomes of a combination regimen consisting of a vasopressor and a vasodilator, such as nitroglycerin.
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Affiliation(s)
- Antonia Stefaniotou
- MSc Program Cardiopulmonary Resuscitation, University of Athens, Medical School, Greece, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Giolanda Varvarousi
- MSc Program Cardiopulmonary Resuscitation, University of Athens, Medical School, Greece, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Dimitrios P Varvarousis
- MSc Program Cardiopulmonary Resuscitation, University of Athens, Medical School, Greece, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Theodoros Xanthos
- MSc Program Cardiopulmonary Resuscitation, University of Athens, Medical School, Greece, 75 Mikras Asias Street, 11527 Athens, Greece.
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Biecker E. Portal hypertension and gastrointestinal bleeding: Diagnosis, prevention and management. World J Gastroenterol 2013; 19:5035-5050. [PMID: 23964137 PMCID: PMC3746375 DOI: 10.3748/wjg.v19.i31.5035] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/21/2013] [Revised: 03/20/2013] [Accepted: 05/17/2013] [Indexed: 02/06/2023] Open
Abstract
Bleeding from esophageal varices is a life threatening complication of portal hypertension. Primary prevention of bleeding in patients at risk for a first bleeding episode is therefore a major goal. Medical prophylaxis consists of non-selective beta-blockers like propranolol or carvedilol. Variceal endoscopic band ligation is equally effective but procedure related morbidity is a drawback of the method. Therapy of acute bleeding is based on three strategies: vasopressor drugs like terlipressin, antibiotics and endoscopic therapy. In refractory bleeding, self-expandable stents offer an option for bridging to definite treatments like transjugular intrahepatic portosystemic shunt (TIPS). Treatment of bleeding from gastric varices depends on vasopressor drugs and on injection of varices with cyanoacrylate. Strategies for primary or secondary prevention are based on non-selective beta-blockers but data from large clinical trials is lacking. Therapy of refractory bleeding relies on shunt-procedures like TIPS. Bleeding from ectopic varices, portal hypertensive gastropathy and gastric antral vascular ectasia-syndrome is less common. Possible medical and endoscopic treatment options are discussed.
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Gastrointestinal Bleeding in Cirrhotic Patients with Portal Hypertension. ISRN HEPATOLOGY 2013; 2013:541836. [PMID: 27335828 PMCID: PMC4890899 DOI: 10.1155/2013/541836] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 05/30/2013] [Accepted: 06/29/2013] [Indexed: 02/06/2023]
Abstract
Gastrointestinal bleeding related to portal hypertension is a serious complication in patients with liver cirrhosis. Most patients bleed from esophageal or gastric varices, but bleeding from ectopic varices or portal hypertensive gastropathy is also possible. The management of acute bleeding has changed over the last years. Patients are managed with a combination of endoscopic and pharmacologic treatment. The endoscopic treatment of choice for esophageal variceal bleeding is variceal band ligation. Bleeding from gastric varices is treated by injection with cyanoacrylate. Treatment with vasoactive drugs as well as antibiotic treatment is started before or at the time point of endoscopy. The first-line treatment for primary prophylaxis of esophageal variceal bleeding is nonselective beta blockers. Pharmacologic therapy is recommended for most patients; band ligation is an alternative in patients with contraindications for or intolerability of beta blockers. Treatment options for secondary prophylaxis include variceal band ligation, beta blockers, a combination of nitrates and beta blockers, and combination of band ligation and pharmacologic treatment. A clear superiority of one treatment over the other has not been shown. Bleeding from portal hypertensive gastropathy or ectopic varices is less common. Treatment options include beta blocker therapy, injection therapy, and interventional radiology.
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Wells M, Chande N, Adams P, Beaton M, Levstik M, Boyce E, Mrkobrada M. Meta-analysis: vasoactive medications for the management of acute variceal bleeds. Aliment Pharmacol Ther 2012; 35:1267-78. [PMID: 22486630 DOI: 10.1111/j.1365-2036.2012.05088.x] [Citation(s) in RCA: 144] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/18/2012] [Revised: 03/12/2012] [Accepted: 03/14/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Vasoactive medications such as vasopressin, somatostatin and their analogues (terlipressin, vapreotide and octreotide) are commonly used for the treatment of acute variceal bleeding. However, the risks and benefits of these interventions are not well understood. AIM To undertake a meta-analysis of the efficacy of vasoactive medications in patients having acute variceal bleeds. METHODS Randomised controlled trials (RCTs) of vasopressin, somatostatin and their analogues, administered to patients with acute variceal bleeds were identified based on systematic searches of nine electronic databases and multiple sources of grey literature. RESULTS The search identified 3011 citations, and 30 trials with a total of 3111 patients met eligibility criteria. The use of vasoactive agents was associated with a significantly lower risk of 7-day mortality (RR 0.74; 95% CI 0.57-0.95; P = 0.02; I(2) = 0%; moderate quality of evidence), and a significant improvement in haemostasis (RR 1.21, 95% CI 1.13-1.30; P < 0.001; I(2) = 28%; very low quality of evidence), lower transfusion requirements (pooled mean difference -0.70 units of blood transfused, 95% CI -1.01 to -0.38; P < 0.001; I(2) = 82%; moderate quality of evidence), and a shorter duration of hospitalisation (pooled mean difference -0.71 days; 95% CI -1.23 to -0.19; P = 0.007; I(2) = 0%; low quality of evidence). Studies comparing different vasoactive agents did not show a difference in efficacy, although the quality of evidence was very low. CONCLUSIONS The use of vasoactive agents was associated with a significantly lower risk of acute all-cause mortality and transfusion requirements, and improved control of bleeding and shorter hospital stay. Studies comparing different vasoactive medications failed to demonstrate a difference in efficacy.
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Affiliation(s)
- M Wells
- Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
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Terlipressin, a provasopressin drug exhibits direct vasoconstrictor properties: consequences on heart perfusion and performance. Crit Care Med 2009; 37:876-81. [PMID: 19237891 DOI: 10.1097/ccm.0b013e31819b8199] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Terlipressin has been proposed as an alternative treatment to catecholamines to restore blood pressure in septic shock. Terlipressin is considered as a vasopressin prodrug capable of releasing small but sustained amounts of [Lysine] vasopressin (LVP) and to provide prolonged biological effect. However, terlipressin may act as a direct vasopressor beyond its conversion into LVP. We investigated terlipressin direct vasoconstrictive properties and consequences on myocardial perfusion and performance. DESIGN Experimental studies. SETTINGS National Research Institute Laboratories. SUBJECTS Rat aorta and heart, human uterine artery. INTERVENTIONS Studies of vasoconstriction on isolated vascular rings obtained either from rat aorta or human uterine artery, and of coronary flow, ventricular performance, and heart rhythm on rat hearts using a modified Langendorff heart apparatus. MEASUREMENTS AND MAIN RESULTS Terlipressin induced a rapid, saturable, and dose-dependent contraction of rat aortas and human uterine arteries. Although the maximal terlipressin-induced vasoconstriction observed on rat arteries was weaker than LVP, or arginine-vasopressin, pharmacologic properties on human arteries, such as full agonism and strong maximal effect (900% of the maximal response obtained with phenylephrine), suggest a high potential of terlipressin to directly vasoconstrict human vessels. Similarly, terlipressin induced a saturable and dose-dependent vasoconstriction of coronary arteries that was reversible and antagonized by selective V1a antagonists. Maximum rates of left ventricle pressure rise (dP/dtmax) and fall (dP/dtmin) decreased both only in proportion to the decrease in coronary flow. CONCLUSIONS Besides long lasting effect through slow conversion into LVP, terlipressin is a fast acting vasopressor peptide per se that has an impact on coronary circulation and myocardial function.
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Krag A, Borup T, Møller S, Bendtsen F. Efficacy and safety of terlipressin in cirrhotic patients with variceal bleeding or hepatorenal syndrome. Adv Ther 2008; 25:1105-40. [PMID: 19018483 DOI: 10.1007/s12325-008-0118-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/15/2022]
Abstract
Terlipressin is an analog of the natural hormone arginine-vasopressin. It is used in the treatment of patients with cirrhosis and bleeding esophageal varices (BEV) and in patients with hepatorenal syndrome (HRS): two of the most dramatic and feared complications of cirrhosis. Terlipressin exerts its main pharmacological effect through stimulation of vasopressin-1 receptors. These receptors are located in vascular smooth muscle and mediate vasoconstriction. In patients with cirrhosis and portal hypertension, treatment with terlipressin increases mean arterial pressure and decreases portal flow and pressure within minutes of administration. Furthermore, in patients with ascites terlipressin improves glomerular filtration and excretion of sodium. Terlipressin decreases failure of initial hemostasis by 34%, decreases mortality by 34%, and is considered a first-line treatment for BEV, when available. Terlipressin in combination with albumin reverses type 1 HRS in 33%-60% of cases and is the only treatment with proven efficacy in randomized trials. The safety profile is favorable when considering the clinical efficacy and the high mortality of these clinical entities. Adverse events are mostly cardiovascular and related to vasoconstriction. Mortality and withdrawal of terlipressin due to adverse events occurs in less than 1% of cases. Mild adverse events related to terlipressin treatment occur in 10%-20% of patients. The benefit, however, of terlipressin on long-term survival in HRS remains to be determined. At present, treatment with terlipressin and albumin is considered the most efficient therapy and should therefore be recommended for the treatment of type 1 HRS-1.
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J Slater M, E Clarke B. Section Review Anti-infectives: Developments in viral hepatitis during 1995. Expert Opin Ther Pat 2008. [DOI: 10.1517/13543776.6.8.739] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/05/2022]
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Petersen MB. The effect of vasopressin and related compounds at V1a and V2 receptors in animal models relevant to human disease. Basic Clin Pharmacol Toxicol 2006; 99:96-103. [PMID: 16918709 DOI: 10.1111/j.1742-7843.2006.pto_299.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/30/2022]
Abstract
Vasopressin, a neurohypophyseal peptide hormone, is the endogenous agonist at V1a, V1b and V2 receptors. The most important physiological function of vasopressin is the maintenance of water homeostasis through interaction with V2 receptors in the kidney. Vasopressin and related compounds are used in various clinical settings such as acute variceal bleeding associated with portal hypertension, septic shock, diabetes insipidus and coagulation disorders. The effect in the former two indications relates to the V1a receptor, and in the two latter indications the effect relates to the V2 receptor. Vasopressin and related compounds have demonstrated activity in animal models of portal hypertension, sepsis and septic shock, diabetes insipidus and coagulation disorders. The use of the compounds in animal models is reviewed. Generally, the effect of vasopressin and related compounds in animal models reflect the activity in the clinical setting, but in some cases important species differences exist.
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Affiliation(s)
- Mads Bjelke Petersen
- Non-Clinical Development, Ferring Pharmaceuticals A/S, Kaj Fiskers Plads 11, DK-2300 Copenhagen, Denmark.
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14
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Abstract
Portal hypertension is a progressively debilitating complication of cirrhosis and a principal cause of mortality in patients who have hepatic decompensation. During the last few decades, significant clinical advances in the prevention of initial variceal hemorrhage, the management of acute variceal hemorrhage, and the prevention of recurrent variceal hemorrhage have reduced the morbidity and mortality of this lethal complication of cirrhosis. This article discusses the pharmacologic treatment of portal hypertension, including preprimary prophylaxis, prevention of a first variceal hemorrhage, treatment of acute variceal hemorrhage, and secondary prophylaxis of a variceal hemorrhage.
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Affiliation(s)
- Melissa A Minor
- Department of Medicine, Division of Gastroenterology and Hepatology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
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15
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Plessier A. Comment traiter une hémorragie digestive aiguë par rupture de varices oesophagiennes. GASTROENTÉROLOGIE CLINIQUE ET BIOLOGIQUE 2004; 28 Spec No 2:B15-20. [PMID: 15150493 DOI: 10.1016/s0399-8320(04)95236-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 10/28/2022]
Affiliation(s)
- Aurélie Plessier
- Service d'Hépatologie, Hôpital Beaujon, 100, boulevard du Général Leclerc, 92110 Clichy
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16
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Abstract
Portal hypertension bleeding is a common and serious complication of cirrhosis. All patients with cirrhosis should undergo endoscopy and be evaluated for possible causes of current or future portal hypertensive bleeding. Possible causes of bleeding include esophageal varices, gastric varices, and PHG. Patients with esophageal varices at high risk of bleeding should be treated with nonselective beta-blockers for primary prevention of variceal hemorrhage. HVPG measurements represent the optimal way to monitor the success of pharmacologic therapy. EVL may be used in those with high-risk varices who do not tolerate beta-blockers. When active bleeding develops, simultaneous and coordinated attention must be given to hemodynamic resuscitation, prevention and treatment of complications, and active control of bleeding. In cases of acute esophageal variceal (Fig. 5) and PHG bleeding, terlipressin, somatostatin, or octreotide should be started. Endoscopic treatment is provided for those with bleeding esophageal varices. If first-line therapy fails, TIPS or surgery may need to be performed. Unlike esophageal variceal or PHG bleeding, there is no established optimal treatment for gastric variceal bleeding. Individual and specific treatment modalities for acute gastric variceal bleeding must be calculated carefully after considering side effects.
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Affiliation(s)
- Kevin M Comar
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, MCV Box 980711, Sanger Hall 12011, Richmond, VA 23298-0711, USA
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17
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Hillert C, Fischer L, Broering DC, Rogiers X. Liver transplantation in patients with liver cirrhosis and esophageal bleeding. Langenbecks Arch Surg 2003; 388:150-4. [PMID: 12756568 DOI: 10.1007/s00423-003-0378-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/01/2003] [Accepted: 04/02/2003] [Indexed: 02/07/2023]
Abstract
BACKGROUND Uncontrolled hemorrhage from esophageal varices is one of the most devastating complications of portal hypertension in patients with advanced cirrhosis. METHODS Drug therapy, endoscopic therapy, transjugular intrahepatic portosystemic shunt (TIPS), or surgical shunts are used with increasing success in the prevention and treatment of bleeding. However, all these treatment modalities have limitations because they do not treat the liver cirrhosis itself. On the other hand, treatment modalities for variceal bleeding may influence the ease of the feasibility of the transplantation procedure. This is particularly the case for surgical treatments like portosystemic shunts and devascularization operations. For this reason these procedures should be avoided if possible. When positioned correctly, a TIPS provides an elegant way of treating portal hypertension without influencing the course of liver transplantation. Liver transplantation offers a treatment that cures both the portal hypertension and the liver disease. However, the use of this method of treatment is limited by the organ availability and by the organ allocation algorithm, resulting in considerable waiting time. CONCLUSION In conclusion, esophageal bleeding should be noticed as an early warning factor, leading the hepatologist to consider liver transplantation and early listing of the patient.
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Affiliation(s)
- Christian Hillert
- Transplantation Center, Department of Hepatobiliary Surgery and Transplantation, University Hospital Hamburg, Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
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18
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Abstract
BACKGROUND Controversy exists surrounding pharmacological therapy in acute variceal bleeding. AIM To determine the efficacy and safety of terlipressin. METHODS Randomized trials were identified and duplicate, independent, review identified 20 randomized trials involving 1609 patients that compared terlipressin with placebo, balloon tamponade, endoscopic treatment, octreotide, somatostatin or vasopressin for treatment of acute oesophageal variceal haemorrhage. RESULTS Meta-analysis showed that compared to placebo, terlipressin reduced mortality (relative risk 0.66, 95% CI 0.49-0.88), failure of haemostasis (relative risk 0.63, 95% CI 0.45-0.89) and the number of emergency procedures per patient required for uncontrolled bleeding or rebleeding (relative risk 0.72, 95% CI 0.55-0.93). When used as an adjuvant to endoscopic sclerotherapy, terlipressin reduced failure of haemostasis (relative risk 0.75, 95% CI 0.58-0.96), and had an effect on reducing mortality that approached statistical significance (relative risk 0.74, 95% CI 0.53-1.04). No significant difference was demonstrated between terlipressin and endoscopic sclerotherapy, balloon tamponade, somatostatin or vasopressin. Haemostasis was achieved more frequently with octreotide compared to terlipressin (relative risk 1.62, 95% CI 1.05-2.50), but this result was based on unblinded studies. Adverse events were similar between terlipressin and the other comparison groups except for vasopressin, which caused more withdrawals due to adverse events. CONCLUSIONS Terlipressin is a safe and effective treatment for acute oesophageal variceal bleeding, with or without adjuvant endoscopic sclerotherapy. Terlipressin appears to reduce mortality in acute oesophageal variceal bleeding compared to placebo, and is the only pharmacological agent shown to do so. Future studies will be required to detect potential mortality differences between terlipressin and other therapeutic approaches.
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Affiliation(s)
- G N Ioannou
- Department of Medicine, Division of Gastroenterology, University of Washington Medical Center, Seattle, WA, USA
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19
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Abstract
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.
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Affiliation(s)
- N Garcia
- Department of Medicine, Gastroenterology, and Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA
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20
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Lee WC, Lin HC, Yang YY, Hou MC, Lee FY, Chang FY, Lee SD. Hemodynamic effects of a combination of prazosin and terlipressin in patients with viral cirrhosis. Am J Gastroenterol 2001; 96:1210-6. [PMID: 11316172 DOI: 10.1111/j.1572-0241.2001.03705.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Terlipressin reduces portal pressure in cirrhotic patients mainly through intense splanchnic vasoconstriction that decrease portal venous inflow. Hepatic blood flow may also be reduced by terlipressin. Prazosin (an alpha1-adrenoceptor antagonist) has also been proposed to decrease portal pressure in cirrhotic patients possibly through a decrease in the intrahepatic vascular resistance. The current study was aimed to evaluate whether a combination of prazosin and terlipressin exerts more beneficial effects than terlipressin alone. METHODS Patients were randomly assigned to receive either a placebo (n = 12) or an oral administration of prazosin 2 mg (n = 12). Thereafter, each patient received an intravenous injection of terlipressin 2 mg. Hemodynamic values were measured basally, 30 min after prazosin or placebo, and 30 min after terlipressin. RESULTS Placebo administration did not affect any hemodynamic values. Terlipressin administration, on the other hand, resulted in expected changes on the hepatic venous pressure gradient, hepatic blood flow, and systemic hemodynamics. In contrast, prazosin significantly decreased hepatic venous pressure gradient with an increased hepatic blood flow and intrinsic hepatic clearance. After terlipressin administration, a further decrease in hepatic venous pressure gradient was observed with preservation of hepatic blood flow and intrinsic hepatic clearance. The magnitude of decrease in hepatic venous pressure gradient was more profound in patients receiving prazosin plus terlipressin than in those receiving terlipressin alone. However, the magnitude of changes in systemic hemodynamics was no different between the two groups of patients. CONCLUSIONS The current study showed that a combination of prazosin and terlipressin resulted in a more profound reduction of hepatic venous pressure gradient with a preservation of hepatic blood flow and intrinsic hepatic clearance than did terlipressin alone. However, the combined therapy did not modify the systemic hemodynamic effects exerted by terlipressin.
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Affiliation(s)
- W C Lee
- Department of Medicine, Taipei Veterans General Hospital, Taiwan
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21
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Abstract
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.
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Affiliation(s)
- P Vlavianos
- Department of Gastroenterology, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK
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22
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Abstract
BACKGROUND 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. OBJECTIVES To determine if treatment with terlipressin improves outcome in acute esophageal variceal hemorrhage and is safe. SEARCH STRATEGY 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. SELECTION CRITERIA 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. DATA COLLECTION AND ANALYSIS 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. MAIN RESULTS 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. REVIEWER'S CONCLUSIONS 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.
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Affiliation(s)
- G Ioannou
- Department of Gastroenterology, University of Washington, 3805 SW Admiral Way, Seattle, WA 98126, USA.
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23
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Escorsell A, Ruiz del Arbol L, Planas R, Albillos A, Bañares R, Calès P, Pateron D, Bernard B, Vinel JP, Bosch J. Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: the TEST study. Hepatology 2000; 32:471-6. [PMID: 10960437 DOI: 10.1053/jhep.2000.16601] [Citation(s) in RCA: 139] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/17/2022]
Abstract
Failure to control bleeding and early rebleeding account for the high mortality associated with variceal hemorrhage in cirrhosis. We compared endoscopic sclerotherapy to terlipressin, a drug that effectively controls acute bleeding while reducing in-hospital mortality. This multicenter randomized controlled trial included 219 cirrhotic patients admitted for endoscopy-proven acute variceal bleeding and randomized to receive repeated injections of terlipressin during 6 days (n = 105) or emergency sclerotherapy (n = 114). Success was defined as obtaining control of bleeding (24-hour bleeding-free period during the first 48 hours) and lack of early rebleeding (any further bleeding from initial control to 5 days later) and survival during the study. Both groups were similar at inclusion. Failure rate for terlipressin was 33% and 32% for sclerotherapy (not significant [NS]). Early rebleeding was responsible for 43% and 44% of failures, respectively. This high efficacy was observed in both Child-Pugh class A + B and Child-Pugh class C patients. Both treatments were similar regarding transfusion requirements, in-hospital stay, and 6-week mortality (26 vs. 19 patients). Side effects appeared in 20% of patients receiving terlipressin and in 30% of those on sclerotherapy (P =.06); being serious in 4% and 7%, respectively (NS). In conclusion, terlipressin and sclerotherapy are equally highly effective therapies achieving the initial control of variceal bleeding and preventing early rebleeding. Both treatments are safe, but terlipressin is better tolerated. Therefore, terlipressin may represent a first-line treatment in acute variceal bleeding until the administration of elective therapy, especially in hospitals where a skilled endoscopist is not available 24 hours a day.
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Affiliation(s)
- A Escorsell
- Liver Unit and Endoscopy Unit, Hospital Clínic, IDIBAPS, Department of Medicine, University of Barcelona, Spain
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24
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Uriz J, Ginès P, Cárdenas A, Sort P, Jiménez W, Salmerón JM, Bataller R, Mas A, Navasa M, Arroyo V, Rodés J. Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J Hepatol 2000; 33:43-8. [PMID: 10905585 DOI: 10.1016/s0168-8278(00)80158-0] [Citation(s) in RCA: 241] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIM Ornipressin, a vasopressin analog with potent splanchnic vasoconstrictor action, has been shown to reverse hepatorenal syndrome. However, its usefulness in clinical practice is limited by frequent ischemic complications. The aim of this study was to assess the efficacy of terlipressin, an analog of vasopressin with a low profile of side effects, plus albumin in this condition. METHODS Nine consecutive patients with cirrhosis and hepatorenal syndrome were included in a pilot study of terlipressin (0.5-2 mg/4 h i.v.) therapy associated with iv albumin. RESULTS Treatment (9 days, range 5-15) was associated with a marked reduction of serum creatinine (3.9+/-0.7 to 1.3+/-0.1 mg/dl, p<0.001, mean+/-SE). Reversal of hepatorenal syndrome (reduction of creatinine below 1.5 mg/dl) was observed in seven of the nine patients. There was a remarkable improvement in circulatory function, with an increase in mean arterial pressure (68+/-2 to 80+/-4 mmHg, p<0.05) and suppression of vasoconstrictor systems activity (plasma renin activity and plasma norepinephrine decreased from 23+/-12 ng/ml x h and 1549+/-373 pg/ml to 3.5+/-2 ng/ml x h and 373+/-98 pg/ml, respectively, p<0.01 for both). No patient developed signs of intestinal, myocardial or distal ischemia. CONCLUSIONS Terlipressin associated with albumin appears to be a safe and effective treatment of hepatorenal syndrome.
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Affiliation(s)
- J Uriz
- Institut de Malalties Digestives, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi-Sunyer, Catalunya, Spain
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25
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Abstract
At the time of diagnosis of cirrhosis, varices are present in about 60% of decompensated and 30% of compensated patients. The risk factors for the first episode of variceal bleeding in cirrhotic patients are the severity of liver dysfunction, a large size of the varices and the presence of endoscopic red colour signs, but only a third of patients who suffer variceal haemorrhage demonstrate the above risk factors. The only treatment that does not require sophisticated equipment or the skills of a specialist, and is immediately available, is vasoactive drug therapy. Hence, drug therapy should be considered to be the initial treatment of choice and can be administered while the patient is transferred to hospital, as has been done in one recent study. Moreover, drug therapy is no longer considered to be only a 'stop-gap' therapy until definitive endoscopic therapy is performed. Several recent trials have reported an efficacy similar to that of emergency sclerotherapy in the control of variceal bleeding. Furthermore, recent evidence suggests that those patients with high variceal or portal pressure are likely to continue to bleed or re-bleed early, implying that prolonged therapy lowering the portal pressure over several days may be the optimal treatment. Pharmacological treatment with beta-blockers is safe, effective and the standard long-term treatment for the prevention of recurrence of variceal bleeding. The combination of beta-blockers with isosorbide-5-mononitrate needs further testing in randomized controlled trials. The use of haemodynamic targets for the reduction of the HVPG response needs further study, and surrogate markers of the pressure response need evaluation. Ligation has recently been compared with beta-blockers for primary prophylaxis, but there is as yet no good evidence to recommend banding for primary prophylaxis if beta-blockers can be given.
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Affiliation(s)
- L Dagher
- Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital NHS Trust, London, UK
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26
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Romero G, Kravetz D, Argonz J, Bildozola M, Suarez A, Terg R. Terlipressin is more effective in decreasing variceal pressure than portal pressure in cirrhotic patients. J Hepatol 2000; 32:419-25. [PMID: 10735611 DOI: 10.1016/s0168-8278(00)80392-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND/AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- G Romero
- Liver Unit, Hospital de Gastroenterologia Dr Bonorino Udaondo, Buenos Aires, Argentina
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27
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Hansen EF, Strandberg C, Højgaard L, Madsen J, Henriksen JH, Schroeder TV, Becker U, Bendtsen F. Splanchnic haemodynamics after intravenous terlipressin in anaesthetised healthy pigs. J Hepatol 1999; 30:503-10. [PMID: 10190736 DOI: 10.1016/s0168-8278(99)80112-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Terlipressin is used for the treatment of bleeding oesophageal varices. We evaluated the effects of terlipressin on hepatic haemodynamics, with special focus on the interactions between portal venous flow and hepatic arterial flow over time. Secondly, we evaluated the estimated hepatic blood flow by the ICG clearance method against direct measurements of hepatic blood flow. METHODS Eight healthy anaesthetised pigs received terlipressin 1 mg or placebo intravenously in a randomised, blind, cross-over design. Hepatic arterial flow, portal venous flow, systemic haemodynamics, and portal vein diameter were recorded simultaneously. Portal venous flow and hepatic arterial flow were measured by transit time ultrasound flowmetry. Estimated hepatic blood flows at baseline and after terlipressin were compared with the sum of the portal venous flow and hepatic arterial flow. RESULTS Portal venous flow decreased significantly 5 min after administration of terlipressin (p<0.05). At 30 min it had decreased by 34% (p<0.01) and the hepatic arterial flow had increased by 81% (p<0.01). The estimated hepatic blood flow and the hepatic blood flow decreased by 23% (p<0.015). At baseline the estimated hepatic blood flow and the hepatic blood flow correlated significantly (r=0.85, p<0.01), but this correlation disappeared after administration of terlipressin (r=0.06, p=ns). The hepatic blood flow was 12% higher than the estimated hepatic blood flow before and after terlipressin. CONCLUSIONS Terlipressin decreased the portal venous flow, hepatic blood flow, and estimated hepatic blood flow significantly and was accompanied by a substantial increase in hepatic arterial flow. The estimated hepatic blood flow and hepatic blood flow were strongly correlated at baseline, but after terlipressin the correlation disappeared.
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Affiliation(s)
- E F Hansen
- Department of Medical Gastroenterology, Hvidovre Hospital, Denmark.
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28
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D'Amico G, Politi F, Morabito A, D'Antoni A, Guerrera D, Giannuoli G, Traina M, Vizzini G, Pasta L, Pagliaro L. Octreotide compared with placebo in a treatment strategy for early rebleeding in cirrhosis. A double blind, randomized pragmatic trial. Hepatology 1998; 28:1206-14. [PMID: 9794903 DOI: 10.1002/hep.510280507] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022]
Abstract
beta-Blockers and sclerotherapy prevent long-term upper digestive rebleeding in cirrhosis but they seem ineffective for early rebleeding. We compared octreotide with a placebo for the prevention of early rebleeding in cirrhotic patients. After control of acute upper digestive bleeding, 262 consecutive cirrhotic patients were randomized to octreotide 100 microgram subcutaneously three times a day for 15 days (n = 131) or to the placebo (n = 131), in a double blind pragmatic trial in which beta-blockers and/or sclerotherapy were allowed together with the experimental treatment. Separate randomization and analysis were performed according to whether patients were eligible for beta-blockers and/or sclerotherapy (101 placebo, 97 octreotide) or not (30 placebo, 34 octreotide). Rebleeding within 15 days was the primary measure of treatment efficacy; 6-week rebleeding rate was also assessed as a secondary measure. Fifteen-day cumulative proportions of patients rebleeding were 28% in the placebo group and 24% in the octreotide group (P = .40); corresponding figures among the 198 patients eligible to beta-blockers and/or sclerotherapy were 26% and 16% (P = .05) and among the 64 not eligible for these treatments 33% and 49% (P = .29). Among patients eligible to beta-blockers and/or sclerotherapy, a significant reduction of rebleeding episodes (35 vs. 18, P = .03), blood transfusions (75 vs. 50, P = .04), and days of stay in hospital (1,544 vs. 1,190, P = .0001) was also found in the octreotide group: this beneficial effect was confirmed 6 weeks after randomization. Mortality was not affected by octreotide in either group of patients. It is suggested that octreotide may reduce the risk of early rebleeding in cirrhotic patients treated with beta-blockers and/or sclerotherapy after control of acute upper digestive bleeding. Further studies are needed to confirm this result.
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Affiliation(s)
- G D'Amico
- Department of Medicine, Ospedale V Cervello, Palermo, Italy
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29
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Wenzel V, Lindner KH, Mayer H, Lurie KG, Prengel AW. Vasopressin combined with nitroglycerin increases endocardial perfusion during cardiopulmonary resuscitation in pigs. Resuscitation 1998; 38:13-7. [PMID: 9783504 DOI: 10.1016/s0300-9572(98)00063-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/30/2022]
Abstract
Although vasopressin increases vital organ blood flow during cardiopulmonary resuscitation (CPR), endocardial perfusion remains suboptimal. This study was designed to assess the effects of vasopressin versus a combination of vasopressin and nitroglycerin on vital organ blood flow in a porcine model of CPR. After 4 min of cardiac arrest, and 3 min of closed-chest compressions, 14 animals were randomly treated with either 0.4 U/kg vasopressin (n = 7) or 0.4 U/kg vasopressin combined with 5 microg/kg nitroglycerin (n = 7). Coronary and cerebral perfusion pressure as well as left ventricular myocardial blood flow was comparable between groups throughout the experiment. Ninety seconds after drug administration, vasopressin combined with nitroglycerin resulted in comparison with vasopressin alone in significantly higher mean (+/- standard error of the mean) left ventricular endocardial blood flow (78+/-7 vs 51+/-5 ml x min(-1) x 100 g(-1); P < 0.05), and a significantly higher endocardial/epicardial perfusion ratio (0.93+/-0.09 vs 0.57+/-0.06; P < 0.05). Seven of seven animals in the vasopressin group, and four of seven animals in the vasopressin and nitroglycerin group (NS) were resuscitated successfully and survived the 2-h observation period. We conclude that, when compared with vasopressin therapy alone, combined vasopressin and nitroglycerin improved endocardial perfusion significantly immediately after drug administration during CPR.
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Affiliation(s)
- V Wenzel
- Department of Anesthesiology, University of Ulm, Germany.
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Burroughs AK, Planas R, Svoboda P. Optimizing emergency care of upper gastrointestinal bleeding in cirrhotic patients. SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. SUPPLEMENT 1998; 226:14-24. [PMID: 9595599 DOI: 10.1080/003655298750027119] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 02/07/2023]
Abstract
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.
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Affiliation(s)
- A K Burroughs
- Dept. of Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital, London, UK
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Gane EJ, Lo SK, Riordan SM, Portmann BC, Lau JY, Naoumov NV, Williams R. A randomized study comparing ribavirin and interferon alfa monotherapy for hepatitis C recurrence after liver transplantation. Hepatology 1998; 27:1403-7. [PMID: 9581698 DOI: 10.1002/hep.510270530] [Citation(s) in RCA: 125] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection usually recurs after orthotopic liver transplantation (OLT), and most patients develop graft damage. This study compared the efficacy of interferon alfa (IFN-alpha) and ribavirin monotherapies in liver transplant recipients with chronic hepatitis C in the graft. Thirty OLT recipients with chronic hepatitis C were randomized to receive either IFN-alpha (3 MU three times a week) or ribavirin (up to 1.2 g daily) for 24 weeks. Virological, biochemical, and histological responses to treatment were assessed. Twenty-eight patients completed the treatment regimen, two ribavirin-treated patients being withdrawn because of severe hemolysis. Normalization of serum aspartate aminotransferase was achieved in 13 of 14 patients receiving ribavirin (93%) and 6 of 14 patients receiving IFN-alpha (43%; P=.01). Lobular inflammation was reduced in 9/14 ribavirin-treated (64%) and 3 of 14 IFN-alpha-treated patients (21%; P=.05), each of whom had a biochemical response. However, the total histological activity index did not improve in either the interferon (P=.43) or the ribavirin (P=.96) group. Posttreatment viremia levels were significantly reduced in IFN-alpha-treated (P=.05) but not in ribavirin-treated (P=.88) patients. Hemolysis occurred in all ribavirin-treated patients, with serum hemoglobin decreasing to < 10 g/dL in 50%. Total leukocyte and lymphocyte counts decreased significantly during ribavirin treatment (P=.02 and P=.004, respectively). We concluded that in patients with chronic hepatitis C after OLT, IFN-alpha retains an antiviral effect whereas ribavirin is superior in achieving normalization of serum aspartate aminotransferase levels and reducing lobular inflammation, but not the total histological activity index. These findings provide a rationale for combination therapy in the post-OLT setting, although patients must be carefully monitored for hemolysis.
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Affiliation(s)
- E J Gane
- Institute of Liver Studies, King's College School of Medicine and Dentistry, London, UK
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Bernadich C, Bandi JC, Melin P, Bosch J. Effects of F-180, a new selective vasoconstrictor peptide, compared with terlipressin and vasopressin on systemic and splanchnic hemodynamics in a rat model of portal hypertension. Hepatology 1998; 27:351-6. [PMID: 9462630 DOI: 10.1002/hep.510270206] [Citation(s) in RCA: 52] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023]
Abstract
The present study is aimed at characterizing the portal, splanchnic, and systemic circulatory effects of F-180, a new long-acting analog of vasopressin (VP) with selective effect on the vascular (V1) receptor, both in normal rats and in portal-hypertensive animals. In preliminary vasopressor tests, F-180 was 18 times more potent than terlipressin (TP) (164 +/- 10 IU x mmol(-1) vs. 9.2 +/- 1.2 IU x mmol(-1)) and four times less potent than arginine VP (614 +/- 25 IU x mmol(-1)). F-180 had negligible antidiuretic potency, resulting in vascular selectivity (V1/V2) of 858 compared with 1.0 for VP and 2.2 for TP. In portal-hypertensive rats with partial portal vein ligation (PPVL), the vasopressor effect of F-180 was 19 times that of TP on a molar basis (ED50 F-180: 0.54 vs. TP: 10.02 nmol x kg(-1)). At low doses (0.405 nmol x kg(-1)), F-180 significantly reduced portal pressure (PP) (-13.8% +/- 6.7%) and superior mesenteric artery blood flow (SMABF) (-25.6% +/- 4.5%), whereas TP at 8.10 nmol x kg(-1) was required to achieve comparable splanchnic effects; however, this dose caused a significantly greater increase in mean arterial pressure (MAP) than F-180 at 0.405 nmol x kg(-1) (28.2% +/- 2.7% vs. 8.9% +/- 2.7% at 20 minutes; P < .05). F-180 at 0.405 nmol x kg(-1) had effects on PP and SMABF similar to a 30-minute intravenous infusion of VP at 10 mU x kg(-1) in PPVL rats, but VP caused a significantly greater elevation in systemic vascular resistance (SVR) and MAP, and more pronounced reduction in cardiac index (P < .05).
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Affiliation(s)
- C Bernadich
- Hepatic Hemodynamic Laboratory, Hospital Clinic i Provincial, University of Barcelona, Catalunya, Spain
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Abstract
Mechanical and pharmacologic measures intended to increase blood flow to vital organs are the mainstay of therapy for patients in cardiac arrest. Several new cardiopulmonary resuscitation (CPR) techniques as well as novel devices and pharmacologic agents have been developed and tested since the first report of manual closed chested CPR over three decades ago. These recent mechanical and pharmacologic advances in the treatment of cardiac arrest are described. Some of these new techniques, devices, and drug therapies are presently undergoing clinical evaluation in patients in cardiac arrest. While many of these new methods and techniques have shown promise in small clinical trials in humans, none have yet to be found to be conclusively superior to manual closed chested CPR and treatment with standard pharmacologic agents.
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Affiliation(s)
- K G Lurie
- Cardiac Arrhythmia Center, University of Minnesota, Minneapolis 55455, USA.
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Escorsell A, Bandi JC, Moitinho E, Feu F, García-Pagan JC, Bosch J, Rodés J. Time profile of the haemodynamic effects of terlipressin in portal hypertension. J Hepatol 1997; 26:621-7. [PMID: 9075670 DOI: 10.1016/s0168-8278(97)80428-x] [Citation(s) in RCA: 84] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS 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. METHODS 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). RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- A Escorsell
- Dept. of Medicine, University of Barcelona, Spain
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Abstract
The splanchnic circulation is one of the largest vascular regions in man. In the past, this has been difficult to study because of methodological problems. The adapting of noninvasive Doppler techniques has made it possible to develop reproducible measurements of coeliac and superior mesenteric artery blood flow, which are the main contributors to the gastrointestinal vasculature. This has resulted in the further understanding of neurogenic and humoral control of this region in a number of physiological and pathophysiological states, and has contributed towards the knowledge of its pharmacological control. These studies are of relevance to cardiovascular homeostasis and, in particular, systemic blood pressure control which depends upon various factors including responses in different vascular regions. In this review the key physiological factors which influence pharmacological studies on this circulation will be discussed. Examples will be provided, in subjects with cardiovascular and neurological disorders, of how administration of endogenous and exogenous substances, including drugs with specific pharmacological effects, alter human gastrointestinal blood flow. These will include insulin, alcohol, the somatostatin analogue octreotide, the central acting sympatholytic clonidine and the angiotensin II-converting inhibitor captopril. The relevance of these studies to subjects with postural hypotension due to sympathetic denervation and to primary hypertension, in particular, will be discussed.
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Affiliation(s)
- C J Mathias
- Department of Medicine, St Mary's Hospital/Imperial College School of Medicine, London, UK
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Abstract
Therapy with ribavirin for 6-12 months is associated with decreases in serum aminotransferases in some patients with chronic hepatitis C. We have assessed the practicality and safety of prolonged therapy with ribavirin. Six patients with chronic hepatitis C were given 1000-1200 mg of ribavirin daily for 24 months. Serum aminotransferases and hepatitis C virus (HCV) RNA levels were monitored during and after therapy. Liver biopsies were carried out before and at the end of treatment. With therapy, mean serum alanine aminotransferase (ALT) levels fell from 161 U/L to 45 U/L at 12 months and to 39 U/L at 24 months. HCV RNA levels did not change. Liver histology improved in five and was unchanged in one patient. When therapy was stopped, aminotransferases rose to pretreatment levels. Side effects included mild fatigue and headaches. Two patients developed gallstones during therapy, perhaps caused by the chronic haemolysis that occurred in all patients. In conclusion, prolonged therapy with ribavirin can result in sustained improvements in serum aminotransferases and hepatic histology in a proportion of patients with chronic hepatitis C. Ribavirin therapy does not cause decreases in viraemia and, therefore, probably must be continued indefinitely to provide lasting benefit. The advantages of such therapy must be weighed against possible long-term side-effects.
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Affiliation(s)
- J H Hoofnagle
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Abstract
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.
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Affiliation(s)
- R Jutabha
- Department of Medicine, University of California, Los Angeles School of Medicine 90095-1684, USA
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Cattral MS, Krajden M, Wanless IR, Rezig M, Cameron R, Greig PD, Chung SW, Levy GA. A pilot study of ribavirin therapy for recurrent hepatitis C virus infection after liver transplantation. Transplantation 1996; 61:1483-8. [PMID: 8633376 DOI: 10.1097/00007890-199605270-00013] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/01/2023]
Abstract
Ribavirin is a guanosine analogue that normalizes serum liver enzymes in most nontransplant patients with chronic hepatitis C virus (HCV) infection. We conducted an uncontrolled pilot study of ribavirin in 9 liver transplantation recipients that had persistently elevated liver enzymes, active hepatitis by liver biopsy, and HCV RNA in serum by polymerase chain reaction. Ribavirin was given orally at dosages of 800-1200 mg per day for 3 mo. All 9 patients promptly responded to ribavirin: mean (+/- SD) ALT decreased from 392 +/- 377 IU/L immediately before treatment to 199 +/- 185 and 68 +/- 37 IU/L after 1 and 12 weeks of treatment, respectively, complete normalization of enzymes occurred in 4 patients. None of the patients cleared the virus from their serum during therapy, and biochemical relapse occurred in all patients 4 +/- 4.2 weeks after cessation of therapy. The hepatitis activity index of liver biopsy specimens obtained before and at the cessation of therapy was similar. Ribavirin treatment was resumed in 4 patients because of increasing fatigue (2 patients), rising bilirubin (3), or increasing necroinflammation on liver biopsy (2); the biochemical response to the second course of therapy was similar to the first course in all 4 patients. Ribavirin caused reversible hemolysis in all patients, including symptomatic anemia in 3 patients that resolved after reduction of drug dosage. These results suggest that ribavirin may be of benefit in the treatment of HCV infection after liver transplantation. Further studies are needed to determine the optimal dosage and duration of therapy.
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Affiliation(s)
- M S Cattral
- Department of Surgery, Liver Transplant Programme, The Toronto Hospital, University of Toronto, Ontario, Canada
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Levacher S, Letoumelin P, Pateron D, Blaise M, Lapandry C, Pourriat JL. Early administration of terlipressin plus glyceryl trinitrate to control active upper gastrointestinal bleeding in cirrhotic patients. Lancet 1995; 346:865-8. [PMID: 7564670 DOI: 10.1016/s0140-6736(95)92708-5] [Citation(s) in RCA: 171] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/26/2023]
Abstract
Upper gastrointestinal bleeding (GIB) is a major complication in cirrhotic patients. Endoscopy and oesophageal sclerosis are reference treatments and must be done as soon as possible. However, such treatment is not possible unless the patient is admitted to hospital. In a prospective, randomised, double-blind trial, we compared the efficacy of terlipressin combined with glyceryl trinitrate (TER-GTN), administered as early as possible to 76 patients with cirrhosis who had active GIB (84 bleeding episodes). Infusion was done at the patient's home by the physician on the emergency team (a mobile intensive care unit) if the patient had GIB and a history and clinical signs of cirrhosis. Patients received either an intravenous injection (1 to 2 mg) of TER-GTN or a double-placebo injection, and then another injection at 4 and 8 h. Control of bleeding, rebleeding, and mortality rate at days 15 and 42 were evaluated. In most patients, endoscopy confirmed the rupture of oesophageal varices (75.7%). Bleeding control was significantly better in the TER-GTN group (n = 41) than in the double-placebo group (n = 43) (p = 0.034). Mortality due to bleeding episodes was significantly lower in the TER-GTN group than in the double-placebo group at day 15 (p = 0.035) and at day 42 (p = 0.06). There were no serious side-effects. Early administration of TER-GTN lowers the deleterious consequences of prolonged hypovolaemia on the hepatic function of these patients.
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Affiliation(s)
- S Levacher
- Département d'Anesthésie-Réanimation, Centre Hospitalier Universitaire Jean Verdier, Université Paris XIII, Bondy, France
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Affiliation(s)
- G D'Amico
- Divisione di Medicina-Instituto di Clinica Medica R, Università di Palermo, Ospedale V Cervello, Spain
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