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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: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar 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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Satapathy SK, Sanyal AJ. Nonendoscopic management strategies for acute esophagogastric variceal bleeding. Gastroenterol Clin North Am 2014; 43:819-833. [PMID: 25440928 PMCID: PMC4255471 DOI: 10.1016/j.gtc.2014.08.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Acute variceal bleeding is a potentially life-threatening complication of portal hypertension. Management consists of emergent hemostasis, therapy directed at hemodynamic resuscitation, protection of the airway, and prevention and treatment of complications including prophylactic use of antibiotics. Endoscopic treatment remains the mainstay in the management of acute variceal bleeding in combination with pharmacotherapy aimed at reducing portal pressure. This article intends to highlight only the current nonendoscopic treatment approaches for control of acute variceal bleeding.
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Affiliation(s)
- Sanjaya K Satapathy
- Division of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN 38104, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, MCV Box 980341, Richmond, VA 23298-0341, USA.
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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: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar 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] [Scholar 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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Abstract
Portal hypertension is a progressively debilitating complication of cirrhosis and a principal cause of mortality in patients who have hepatic decompensation. This article describes the classification system and pathophysiology of portal hypertension. It also discusses a practical approach to prevention of first variceal hemorrhage, general management of the acute bleeding episode, and secondary prophylaxis to prevent rebleeding. Pharmacologic, endoscopic, radiologic, and surgical modalities are all described in detail.
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Affiliation(s)
- David A Sass
- Division of Gastroenterology and Hepatology, Drexel University College of Medicine, 216 N. Broad Street, Feinstein Building, Suite 504, MS 1001, Philadelphia, PA 19102, USA.
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Chang CC, Wang SS, Huang HC, Lee FY, Lin HC, Lee JY, Chen YC, Lee SD. Chronic thalidomide administration enhances vascular responsiveness to vasopressin in portal-systemic collaterals of bile duct-ligated rats. J Chin Med Assoc 2009; 72:234-42. [PMID: 19467946 DOI: 10.1016/s1726-4901(09)70063-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Arginine vasopressin (AVP) controls gastroesophageal variceal bleeding, partly due to its vasoconstrictive effect on portal-systemic collaterals. It has been shown that chronic thalidomide treatment decreases portal pressure, attenuates hyperdynamic circulation and inhibits vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-alpha in partially portal vein-ligated rats. This study investigated the effects of chronic thalidomide treatment on portal-systemic collateral vascular responsiveness to AVP in common bile duct-ligated (CBDL) cirrhotic rats. METHODS In the first series, CBDL-induced cirrhotic rats received thalidomide (50 mg/kg/day orally) or distilled water (control) from the 35th to 42nd day after ligation. On the 43rd day after ligation, the body weight, mean arterial pressure, portal pressure, and heart rate were measured. An in situ collateral vascular perfusion model was used to obtain the cumulative concentration-response curves of collateral vessels to AVP (10(-10) to 3 x 10(-7) M). Plasma levels of VEGF and TNF-alpha were measured, and expressions of VEGF and TNF-alpha mRNA in the left adrenal veins were also determined. In the second series, the cumulative concentration-response curves of collateral vessels to AVP in CBDL rats with or without thalidomide (10(-5) M) preincubation in the perfusate were obtained. RESULTS The thalidomide and control groups were not significantly different in terms of heart rate, mean arterial pressure and portal pressure (p > 0.05). The collateral vascular perfusion pressure change to AVP was significantly enhanced at 10(-8) M after thalidomide treatment (p = 0.041). Compared with the control group, thalidomide-treated rats had significantly lower plasma VEGF levels (p < 0.001), accompanied by an insignificant reduction in plasma TNF-alpha levels (p > 0.05). The expressions of VEGF and TNF-alpha mRNA in the left adrenal veins of thalidomide-treated CBDL rats were not significantly changed compared with those of the control group. In addition, thalidomide did not significantly elicit changes in vascular responsiveness to AVP in collateral vessels of CBDL rats when it was added into the perfusate. CONCLUSION In cirrhotic rats, chronic thalidomide treatment improves the portal-systemic collateral vascular responsiveness to AVP, which was partly related to VEGF inhibition.
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Affiliation(s)
- Ching-Chih Chang
- Department of Medicine, Taipei Veterans General Hospital, Taiwan, R.O.C
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Hackworth WA, Sanyal AJ. Review: Vasoconstrictors for the treatment of portal hypertension. Therap Adv Gastroenterol 2009. [DOI: 10.1177/1756283x09102330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Vasoconstrictors have long been used in an attempt to mitigate the effects of portal hypertension. In this review, we discuss the current understanding of portal hypertension and the use of vasoconstrictors in the management of its sequlae, including variceal hemorrhage, hepatorenal syndrome, and paracentesis-induced circulatory dysfunction. Experimental and clinical evidence for the use of vasoconstrictors is considered, and several exciting recent developments are reviewed.
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Affiliation(s)
- William A. Hackworth
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J. Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA,
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Dell'Era A, de Franchis R, Iannuzzi F. Acute variceal bleeding: pharmacological treatment and primary/secondary prophylaxis. Best Pract Res Clin Gastroenterol 2008; 22:279-94. [PMID: 18346684 DOI: 10.1016/j.bpg.2007.11.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Variceal bleeding is one of the most severe complications of portal hypertension related to liver cirrhosis. Primary prophylaxis is considered mandatory in patients with cirrhosis and high-risk oesophageal varices, and once varices have bled, every effort should be made to arrest the haemorrhage and prevent further bleeding episodes. In acute variceal bleeding, vasoactive drugs that lower portal pressure should be started even before endoscopy, and should be maintained for up to 5 days. The choice of vasoactive drug should be made according to local resources. Terlipressin, somatostatin and octreotide can be used; vasopressin plus transdermal nitroglycerin may be used if no other drug is available. In variceal bleeding, antibiotic therapy is also mandatory. In primary and secondary prophylaxis, beta-blockers are the mainstay of therapy. In secondary prophylaxis (but not in primary prophylaxis) these drugs can be combined with organic nitrates.
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Affiliation(s)
- A Dell'Era
- Department of Medical Sciences, University of Milano, and Gastroenterology 3 Unit, IRCCS Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena Foundation, Via Pace 9, 20122 Milano, Italy
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Abstract
Variceal bleeding is a frequent and life-threatening complication of portal hypertension. The first episode of variceal bleeding is associated not only with a high mortality, but also with a high recurrence rate in those who survive. Therefore, management should focus on different therapeutic strategies aiming to prevent the first episode of variceal bleeding (primary prophylaxis), to control hemorrhage during the acute bleeding episode (emergency treatment), and to prevent rebleeding (secondary prophylaxis). These strategies involve pharmacological, endoscopic, surgical, and interventional radiological modalities. This article reviews management of acute variceal bleeding.
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Affiliation(s)
- Adil Habib
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University Medical Center, MCV Box 980341, Richmond, VA 23298-0341, USA
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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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Rockey DC. Pharmacologic therapy for gastrointestinal bleeding due to portal hypertension and esophageal varices. Curr Gastroenterol Rep 2006; 8:7-13. [PMID: 16510029 DOI: 10.1007/s11894-006-0058-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cirrhosis results in portal hypertension in many patients. The major complications of portal hypertension include development of ascites and esophageal or gastric varices. Varices lead to hemorrhage and death in a significant proportion of patients. This review focuses on the pharmacologic approach to management of portal hypertension in patients at risk of variceal hemorrhage, or those who have already had variceal bleeding. Pharmacologic therapy is used for 1) primary prevention of bleeding, 2) management of acute bleeding, and 3) prevention of recurrent bleeding (secondary prophylaxis). For acute esophageal variceal hemorrhage, a variety of pharmacologic agents are used, including somatostatin, octreotide, vapreotide, lanreotide, terlipressin, and vasopressin (with nitrates). For primary and secondary prevention of esophageal variceal hemorrhage, beta-blockers remain the mainstay therapy.
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Affiliation(s)
- Don C Rockey
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8887, USA.
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Abstract
Variceal bleeding is one of the dreaded complications of portal hypertension. Patients who have suspected or proven cirrhosis should undergo diagnostic upper endoscopy to detect medium and large gastro-esophageal varices. Patients with medium and large gastro-esophageal varices should be treated with non-selective beta-blockers (propranolol or nadolol), and these agents should be titrated to a heart rate of 55 beats per minute or adverse effects. If there are contraindications to or if patients are intolerant to beta-blockers, it is appropriate to consider prophylactic banding therapy for individuals with medium-to-large esophageal varices. When patients who have cirrhosis present with GI bleeding, they should be resuscitated and receive octreotide or other vasoactive agents. Endoscopy should be performed promptly to diagnose the source of bleeding and to provide endoscopic therapy (preferably banding). The currently available treatment for acute variceal bleeding provides hemostasis in most patients. These patients, however, are at significant risk for rebleeding unless secondary prophylaxis is provided. Although various pharmacological, endoscopic, radiological, and surgical options are available, combined pharmacological and endoscopic therapy is the most common form of secondary prophylaxis. TIPS is a radiologically placed portasystemic shunt, and if placed in suitable patients, it can provide effective treatment for patients with variceal bleeding that is refractory to medical and endoscopic therapy.
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Affiliation(s)
- Atif Zaman
- Oregon Health Sciences University, Portland, 97239, USA
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Morales J, Moitinho E, Abraldes JG, Fernández M, Bosch J. Effects of the V1a vasopressin agonist F-180 on portal hypertension-related bleeding in portal hypertensive rats. Hepatology 2003; 38:1378-83. [PMID: 14647048 DOI: 10.1016/j.hep.2003.09.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
F-180 is a new, long-acting analog of vasopressin with a selective agonist effect on the vascular V1a receptors, with the advantage of having no effect on renal V2 receptors. F-180 is approximately 20 times more powerful than terlipressin in reducing portal pressure and has less marked systemic effects. The present study investigated the effects of F-180 on the outcome of portal hypertension-related bleeding in hypovolemic rats. Partial portal vein-ligated rats were subjected to portal hypertension-related bleeding by sectioning a first-order branch of the ileocolic vein. After hemodynamic stabilization, a second sectioning of the first-order branch of the ileocolic vein section was performed in the already hypovolemic animals, and either F-180 or placebo was administered. Blood transfusion was adjusted to maintain mean arterial pressure (MAP) gamma > 80 mm Hg. The first section of a first-order branch of the ileocolic vein induced a hemorrhage of similar severity in both groups of rats. After a 2nd sectioning of a first-order branch of the ileocolic vein section, F-180 was more effective than placebo in recovering shock (MAP, 21% +/- 23% vs. 0% +/- 13% in placebo; P <.05), preventing portal pressure (PP) increase during blood transfusion (PP: -1% +/- 19% vs. 47% +/- 65% in placebo; P =.07), reducing transfusion requirements (2.9 +/- 3.3 mL vs. 11.2 +/- 6.0 mL in placebo; P <.01), diminishing the magnitude of collected blood losses (5.1 +/- 2.2 g vs. 12.7 +/-7.7 g in placebo; P <.05), and decreasing the mortality from the portal hypertension-related bleeding (10% vs. 60% in placebo; P <.05). In conclusion, in hypovolemic portal-hypertensive rats during a portal hypertension-related bleeding, F-180 rapidly recovers arterial pressure and decreases transfusion requirements, blood losses, and mortality.
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Affiliation(s)
- Josephine Morales
- Hepatic Hemodynamic Laboratory, Liver Unit, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
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Lee HY, Lee HJ, Lee SM, Kim JH, Kweon SW, Lee BS, Kim NJ. A prospective randomized controlled clinical trial comparing the effects of somatostatin and vasopressin for control of acute variceal bleeding in the patients with liver cirrhosis. Korean J Intern Med 2003; 18:161-6. [PMID: 14619385 PMCID: PMC4531632 DOI: 10.3904/kjim.2003.18.3.161] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Acute variceal bleeding is a serious complication of liver cirrhosis, which has an attendant mortality of approximately 60% over two years, and a variety of treatments, such as balloon tamponade, endoscopic varix ligation, sclerotherapy, histoacryl injection and vasoactive drugs, have been used. The aims of the present trial were to compare the effectiveness and complications of somatostatin and vasopressin in the treatment of acute variceal bleeding. METHODS Forty-three cirrhotic patients, with endoscopically proven acute variceal bleeding, were included in this trial. Both drugs were given as continuous intravenous infusions for 48 hours. Twenty patients received the somatostatin (250 mcg per hr after a bolus of 50 mcg) and twenty-three the vasopressin (0.4 units per min). RESULTS There were no significant differences between the two groups in relation to age, sex, etiology of cirrhosis, Child-Pugh classification, characteristics of bleeding episode, laboratory findings before randomization and units of transfused blood during therapy. Rebleeding, within 6 hours after beginning of therapy, was regarded as failure to control initial bleeding, and was observed in 3 (13.0%) of the patients who received vasopressin and in 1 (5.0%) treated with somatostatin (p > 0.05). Five patients in both the somatostatin (25.0%) and vasopressin (21.7%) groups rebled during the first 5 days following the initial therapy (p > 0.05). Meaningful complications related to the use of vasopressin were observed in 5 patients (chest pain or abdominal pain requiring nitroglycerin), but no complications were associated with the use of somatostatin (p < 0.05). The mortalities during hospitalization were similar in both the treatment groups. Two of the vasopressin and 1 of the somatostatin group died due to the uncontrolled rebleeding, and 1 of the vasopressin group died due to hepatic failure (2 weeks later after therapy). CONCLUSION This study showed no differences in the effectiveness of somatostatin and vasopressin, but the somatostatin group had a lower risk of the complications.
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Affiliation(s)
- Heon Young Lee
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea.
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Abstract
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.
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Affiliation(s)
- J W Ferguson
- Liver Unit, New Royal Infirmary of Edinburgh, Edinburgh, UK.
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Vaughan RB, Chin-Dusting JPF. Current pharmacotherapy in the management of cirrhosis: focus on the hyperdynamic circulation. Expert Opin Pharmacother 2003; 4:625-37. [PMID: 12739989 DOI: 10.1517/14656566.4.5.625] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Many major complications of hepatic cirrhosis relate to the development of a characteristic hyperdynamic circulatory state in these patients, irrespective of the underlying disease aetiology. Vasodilatation of the systemic and splanchnic circulations leads to a reduced total systemic vascular resistance, increased cardiac output and intense activation of neurohumoral vasoconstrictor systems including the sympathetic nervous system, renin-angiotensin system and vasopressin. Vasoconstriction of the renal and hepatic circulations contributes to the development of renal failure and portal hypertension, respectively. Current treatments that focus on amelioration of these circulatory derangements offer much promise, however, they are often limited by side effects in these patients.
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Affiliation(s)
- Rhys B Vaughan
- Wynn Domain, Baker Heart Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia
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Wang SS, Chan CC, Lee FY, Chang FY, Lin HC, Chen CT, Huang HC, Tai CC, Lai IN, Lee SD. Effects of long-term octreotide treatment on the response of portal-systemic collaterals to vasopressin in portal hypertensive rats. Eur J Clin Invest 2002; 32:316-21. [PMID: 12027870 DOI: 10.1046/j.1365-2362.2002.00987.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Chronic portal hypertension is associated with the development of portal-systemic collaterals. Long-term octreotide treatment has been shown to enhance the constrictive response to vasopressin in the mesenteric arteries of portal hypertensive rats. This study investigated the effects of long-term octreotide treatment on the response of portal-systemic collaterals to vasopressin in portal hypertensive rats. METHODS Partially portal vein-ligated rats were divided into two groups to receive subcutaneous injection of either placebo (5% dextrose in water) or octreotide (30 microg kg(-1)) twice daily for 7 days. Two series of experiments were performed to measure: (a) the systemic and portal hemodynamics and cumulative concentration-response curves of collateral vessels to vasopressin (10(-10) to 10(-7 )M) and (b) the slopes of the flow-pressure curves of collaterals (an index of portal-systemic shunting). The cumulative concentration-response curves and flow pressure curves were determined by the in situ collateral perfusion. RESULTS Long-term octreotide treatment significantly lowered the portal pressure without changes in the mean arterial pressure. Vasopressin significantly and similarly increased the perfusion pressure of collateral vessels in both the placebo- and octreotide-treated groups. In addition, long-term octreotide treatment exerted no effect on the EC(50) of vasopressin (-8.25 +/- 0.19 vs. -8.20 +/- 0.10, P > 0.05) and the slopes of flow-pressure curves (0.97 +/- 0.02 vs. 0.94 +/- 0.04, P > 0.05) in the collaterals. CONCLUSION Despite lowering the portal pressure, long-term octreotide treatment did not enhance the vasoconstrictive effect of vasopressin in the collateral vessels of portal hypertensive rats and ameliorate the degree of portal-systemic shunting.
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Affiliation(s)
- S-S Wang
- Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China.
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19
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Coto E, Rodrigo L, Alvarez R, Fuentes D, Rodríguez M, Menéndez LG, Ciriza C, González P, Alvarez V. Variation at the Angiotensin-converting enzyme and endothelial nitric oxide synthase genes is associated with the risk of esophageal varices among patients with alcoholic cirrhosis. J Cardiovasc Pharmacol 2001; 38:833-9. [PMID: 11707686 DOI: 10.1097/00005344-200112000-00004] [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] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Esophageal varices are a frequent complication among patients with liver cirrhosis. Nitric oxide and other vasoactive molecules regulate the vascular tone in both the liver microcirculation and the systemic and splanchnic circulation. Several genes that encode proteins involved in the maintenance of vascular tone, such as the endothelial-constitutive nitric oxide synthase (ecNOS), the angiotensinogen (AGT), the angiotensin-converting enzyme (ACE), and the angiotensin II receptor type 1 (AT1R) are polymorphic, and these polymorphisms have been associated with several cardiovascular diseases. Our aim was to define a possible role for DNA polymorphisms at these genes in the risk of developing esophageal varices among patients with alcoholic cirrhosis. We analyzed 145 male patients with liver cirrhosis. Patients and 200 healthy controls were genotyped by polymerase chain reaction for the ACE-I/D, the AGT-M235T, the AT1R-A1166C, and the ecNOS-4/5 (intron 4) polymorphisms. Ninety-five patients had varices and 50 did not show this complication. Carriers of the ACE-I allele (ID + II genotypes) were at a significantly higher frequency among patients with varices (p = 0.013). Patients without varices had a higher frequency of the ecNOS-4 allele compared with patients with varices (p = 0.026). ACE-I carriers + ecNOS-55 were at a significantly higher frequency (p = 0.0012; odds ratio = 3.19; 95% CI = 1.55-6.55) among patients with varices (51 of 95, 54%) compared with patients without (18 of 50, 36%). Allele and genotype frequencies for the AGT and AT1R polymorphisms did not differ between the two groups. The genotypes associated with an increased risk for varices have been linked to higher plasma levels of nitric oxide and reduced levels of ACE. These genotypes could have a vasodilatory effect in the systemic and splanchnic circulation, thus favoring the development of portocollaterals.
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Affiliation(s)
- E Coto
- Molecular Genetics-IRSIN and Digestive Service, Central Hospital of Asturias, Oviedo, Spain.
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Affiliation(s)
- A I Sharara
- Department of Medicine, American University of Beirut Medical Center, Lebanon
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21
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Abstract
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.
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Affiliation(s)
- V A Luketic
- Division of Gastroenterology, Medical College of Virginia Commonwealth University, Richmond, Virginia, USA.
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22
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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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23
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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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24
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Luketic VA, Sanyal AJ. Esophageal varices. I. Clinical presentation, medical therapy, and endoscopic therapy. Gastroenterol Clin North Am 2000; 29:337-85. [PMID: 10836186 DOI: 10.1016/s0889-8553(05)70119-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
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.
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Affiliation(s)
- V A Luketic
- Department of Medicine, Medical College of Virginia Commonwealth University, Richmond, USA.
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25
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Abstract
Transjugular intrahepatic protosystemic shunts (TIPS) is the newest and the least invasive method of eradicating varices. This article defines portal hypertension succinctly, describes how it gives rise to varices and their consequences, and briefly reviews the development, short experience with, and current status of TIPS.
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Affiliation(s)
- H O Conn
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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26
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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] [Scholar 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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27
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Patch D, Burroughs AK. Advances in drug therapy for acute variceal haemorrhage. BAILLIERE'S CLINICAL GASTROENTEROLOGY 1997; 11:311-26. [PMID: 9395750 DOI: 10.1016/s0950-3528(97)90042-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
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.
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Affiliation(s)
- D Patch
- Department of Liver Transplantation and Hepato-Biliary Medicine, Royal Free Hampstead NHS Trust, Hampstead, London, UK
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28
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García-Pagán JC, Bosch J. Pharmacological prevention of variceal bleeding. New developments. BAILLIERE'S CLINICAL GASTROENTEROLOGY 1997; 11:271-87. [PMID: 9395748 DOI: 10.1016/s0950-3528(97)90040-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The introduction of pharmacological therapy has been one of the major advances in the treatment of the complications of portal hypertension. Many drugs have been shown to reduce portal hypertension in patients with cirrhosis. However, the most widely used drugs and the only ones for which there is sufficient evidence, are the beta-blockers. These drugs have been, up to now, the only accepted prophylactic therapy for oesophageal variceal bleeding and are also an alternative treatment to sclerotherapy or surgery to prevent variceal rebleeding. A reduction in portal pressure gradient by beta-blockers below 12 mmHg or by more than 20% of baseline values is associated with almost a total protection from oesophageal bleeding. Such a marked response in portal pressure is only achieved in some patients receiving propranolol. New pharmacological approaches with a greater portal pressure reducing effect may improve the beneficial effect of drugs in preventing variceal bleeding. The more promising approach is the combined administration of beta-blockers and isosorbide-5-mononitrate, which has been shown to potentiate the reduction in portal pressure and to be highly effective in initial randomized clinical trials.
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Affiliation(s)
- J C García-Pagán
- Department of Medicine, Hospital Clínic i Provincial, University of Barcelona, Spain
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29
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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: 93] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar 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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30
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Hori N, Okanoue T, Sawa Y, Mori T, Kashima K. Haemodynamic effects of combined treatment with molsidomine and propranolol on portal hypertension in conscious and unrestrained cirrhotic rats. J Gastroenterol Hepatol 1996; 11:985-92. [PMID: 8912139 DOI: 10.1111/j.1440-1746.1996.tb01858.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We investigated the systemic and splanchnic haemodynamic effects of combined treatment with molsidomine and propranolol on cirrhotic rats. Liver cirrhosis was produced by repeated intraperitoneal injections of thioacetamide. The blood flow of each organ was measured serially using the radioactive microsphere method in the awake state before and after the administration of each agent. Cirrhotic rats received molsidomine (0-.5 mg/kg), propranolol (0.1 or 0.2 mg/min), both agents or placebo. Combination treatment with molsidomine and 0.1 mg/min propranolol significantly reduced portal pressure compared with molsidomine or propranolol alone (21 +/- 4 vs 15 +/- 3 or 11 +/- 2% P < 0.05). Systemic haemodynamic changes with this combined treatment were mild. This combined treatment slightly inhibited the molsidomine-induced decrease in portal vascular resistance (27 +/- 9 vs 31 +/- 6; NS) and markedly inhibited the molsidomine-induced decrease in splanchnic arterial resistance (7 +/- 6 vs 27 +/- 5% P < 0.05). Compared with low-dose propranolol administration, the combined treatment was associated with a significant decrease in portal vascular resistance (27 +/- 9% decrease vs 2 +/- 2% increase; P < 0.001) and a significant decrease in splanchnic arterial resistance (7 +/- 6% decrease vs 5 +/- 4% increase P < 0.05). The combination of molsidomine and high-dose propranolol (0.2 mg/min) caused a marked reduction in portal venous inflow, mean arterial pressure and cardiac index. We conclude that propranolol enhances the molsidomine-induced decrease in portal pressure by splanchnic vasoconstriction in association with a slight decrease in portal vascular resistance. The combination therapy with molsidomine and low-dose propranolol combination had more beneficial and less harmful effects on systemic and splanchnic haemodynamics and thus appears to be a superior method for treating portal hypertension.
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Affiliation(s)
- N Hori
- Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan
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31
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Abstract
Portal hypertension results from increases in portal flow and portal vascular resistance. Factors increasing portal blood flow are predominantly humoral. Resistance to portal flow has a fixed component due to distortion of the vasculature by cirrhotic nodules and a variable component that is related to vasoactive substances. Varices result from an increase in portal pressure. Factors predicting the risk of variceal bleeding include continued alcohol use, poor liver function, large varices, and red wale markings on varices at endoscopy. Octreotide is probably the drug of choice for pharmacologic management of bleeding esophageal varices. Propranolol has an established role in the prevention of variceal hemorrhage, and variceal band ligation may be the preferred endoscopic technique. Transjugular intrahepatic portosystemic shunts have emerged as an important treatment for patients in whom pharmacologic and endoscopic therapies have failed and are an effective bridge to liver transplantation.
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Affiliation(s)
- L R Roberts
- Division of Gastroenterology and Internal Medicine, Mayo Clinic Rochester, Minnesota 55905, USA
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32
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Sandford NL, Kerlin P. Current management of oesophageal varices. AUSTRALIAN AND NEW ZEALAND JOURNAL OF MEDICINE 1995; 25:528-34. [PMID: 8588778 DOI: 10.1111/j.1445-5994.1995.tb01501.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Patients with chronic liver disease and large varices with endoscopic features which put them at high risk of bleeding, especially if they have a HVPG of more than 12 mmHg, should be treated with beta-blockers at a dose which lowers their pulse by 25%, as prophylaxis against future bleeding. Once a patient bleeds from oesophageal varices, emergency treatment with octreotide should be commenced until endoscopic sclero- or ligation therapy is performed. If these treatments are not readily available, or if bleeding continues in spite of treatment, balloon tamponade is employed to arrest bleeding. In the event of recurrent bleeding, further sclero- or ligation therapy should be attempted, but continued bleeding would dictate surgical therapy or insertion of a TIPS. What operation is performed would depend on the local expertise. In a suitable candidate, liver transplantation would be considered. If bleeding is controlled by sclero- or ligation therapy, chronic sclerotherapy should be continued until the varices are obliterated, and beta-blockers commenced. Regular follow-up should be arranged to encourage abstinence from alcohol if appropriate, and to decide the most opportune time for transplantation if indicated.
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Affiliation(s)
- N L Sandford
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Qld
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33
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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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35
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Bosch J, Bruix J, Mas A, Navasa M, Rodés J. Rolling review: the treatment of major complications of cirrhosis. Aliment Pharmacol Ther 1994; 8:639-57. [PMID: 7696453 DOI: 10.1111/j.1365-2036.1994.tb00342.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- J Bosch
- Liver Unit, Hospital Clínic i Provincial, University of Barcelona, Spain
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36
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Hori N, Okanoue T, Sawa Y, Itoh Y, Mori T, Takami S, Kashima K. Hemodynamic effects of combined treatment with somatostatin analogue (SMS 201-995) and low-dose isosorbide dinitrate on portal hypertension in conscious cirrhotic rats. J Gastroenterol 1994; 29:460-8. [PMID: 7951857 DOI: 10.1007/bf02361244] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The authors investigated whether combined treatment with the somatostatin analogue, SMS 201-995, and low-dose isosorbide dinitrate enhanced the hemodynamic effects of the individual agents on rats with thioacetamide-induced cirrhosis. Four groups of cirrhotic rats received SMS 201-995 (0.1 microgram.min-1.kg-1), isosorbide dinitrate (10 micrograms.min-1.kg-1), both agents, or placebo, respectively. Hemodynamics were measured serially in conscious rats, using a radioactive microsphere method. SMS 201-995 reduced portal venous inflow 21 +/- 4% and portal pressure 17 +/- 3%. Isosorbide dinitrate decreased portal venous inflow 20 +/- 4%, by inducing splanchnic vasoconstriction mediated by low pressure baroreflexes, and this agent also decreased portal pressure, by 14 +/- 2%. Portal venous resistance rose 7.6 +/- 3% with isosorbide dinitrate alone, but decreased 18 +/- 4% with combination therapy. This effect may have been induced by the pronounced vasodilatory effect of isosorbide dinitrate on the venous vasculature, since the reflex splanchnic vasoconstriction that occurs with low-dose isosorbide dinitrate disappears when this agent is combined with SMS 201-995. The decrease in portal pressure was more marked (22 +/- 4%) and changes in systemic hemodynamics were milder with the combined treatment. It was concluded that combination therapy with SMS 201-995 and low-dose isosorbide dinitrate may be beneficial for portal hypertension in liver cirrhosis.
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Affiliation(s)
- N Hori
- Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan
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37
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Affiliation(s)
- P C Bornman
- Groote Schuur Hospital, Observatory, South Africa
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38
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D'Amico G, Traina M, Vizzini G, Tinè F, Politi F, Montalbano L, Luca A, Pasta L, Pagliaro L, Morabito A. Terlipressin or vasopressin plus transdermal nitroglycerin in a treatment strategy for digestive bleeding in cirrhosis. A randomized clinical trial. Liver Study Group of V. Cervello Hospital. J Hepatol 1994; 20:206-12. [PMID: 8006401 DOI: 10.1016/s0168-8278(05)80059-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
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.
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Affiliation(s)
- G D'Amico
- Divisione di Medicina, University of Palermo, Ospedale V Cervello, Italy
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39
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Iwao T, Toyonaga A, Ikegami M, Oho K, Sumino M, Sakaki M, Shigemori H, Nakayama M, Sasaki E, Tanikawa K. Effects of vasopressin and nicardipine on hemodynamics and liver function in patients with cirrhosis: comparison with vasopressin alone. J Hepatol 1993; 19:345-52. [PMID: 8151095 DOI: 10.1016/s0168-8278(05)80542-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The effects of a combination of vasopressin and a calcium channel blocker (nicardipine) on portohepatic hemodynamics and liver function were compared with the effects of vasopressin alone in 18 patients with portal hypertension. Nine patients received 0.4 units/min of vasopressin and 9 patients received the same dose of vasopressin plus 0.3 mg/min of nicardipine for 40 min. Vasopressin plus nicardipine induced a significant reduction in both free portal venous pressure and the portal venous pressure gradient. These effects were similar to the changes with vasopressin alone (-14% vs. -16% in free portal venous pressure; -29% vs. -31% in portal venous pressure gradient). Vasopressin decreased both hepatic blood flow (-34%, P < 0.01) and intrinsic clearance of indocyanine green (-22%, P < 0.05). In contrast, these two parameters did not significantly change after vasopressin plus nicardipine (-8% and -3%, respectively). These results suggest that the addition of nicardipine improves hepatic impairment induced by vasopressin but causes no further reduction on portal pressure.
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Affiliation(s)
- T Iwao
- Second Department of Medicine, Kurume University School of Medicine, Japan
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40
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Abstract
About 30% to 35% of patients with portal hypertension bleed from gastroesophageal varices and mortality remains high reflecting the challenges of effectively dealing with the bleeding event itself and the problems of underlying liver disease. Careful resuscitation and control of risk of complications is the most essential element of medical therapy (Fig. 2). Use of newer, more effective drug combinations with vasopressin or somatostatin permit control of hemorrhage in the majority of patients with fewer drug-induced complications. Endoscopic sclerotherapy and, more recently, banding therapy provide immediate control of hemorrhage and eradication of varices and rebleeding in up to 90% of patients. Persistent, recurrent bleeding in the small number of remaining patients can be effectively managed by "portacaval shunt rescue" or orthotopic liver transplantation in selected cases with acceptable surgical morbidity and mortality. The contribution and role of the TIPS procedure is unknown but very promising; at least as a bridge procedure in patients awaiting transplantation. Until appropriate prospective, comparative trials are performed, the role of TIPS as a long-term alternative to portacaval shunt surgery or other endoscopic or surgical options remains unknown.
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Affiliation(s)
- T G Brewer
- Pharmacology Department, Walter Reed Army Institute of Research, Washington, DC
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41
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Renner EL. Medikamentöse Behandlung der portalen hypertonie. Eur Surg 1993. [DOI: 10.1007/bf02602085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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42
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Abstract
A systematic review of available treatments for controlling active variceal bleeding provides important guidelines for choosing an overall strategy. The initial prerequisite of a diagnostic endoscopy provides the opportunity for early intervention with local endoscopic techniques, such as injection sclerotherapy, direct intravariceal injection of tissue adhesives and banding ligation of varices. This approach currently represents the optimal strategy. If the endoscopic expertise is not available, the use of vasoactive drugs may provide temporary control of bleeding while allowing time for more definitive treatment. Vasopressin and its analogues are the most widely used vasoactive drugs, but somatostatin holds promise. In view of the systemic haemodynamic complications associated with vasopressin (and probably glypressin), these drugs should be given in combination with nitrates. Balloon tamponade remains an important alternative for patients in whom massive, life-threatening haemorrhage has occurred. Surgical techniques, such as shunting and devascularisation, are increasingly reserved for the management of variceal bleeding that endoscopic therapy has failed to control.
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43
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Abstract
The pathogenesis of portal hypertension remains poorly understood. Similarly, pharmacological manipulation for the prevention and treatment of variceal haemorrhage has not fulfilled the promise of the 1980s. This article reviews current concepts in the pathophysiology of portal hypertension and considers pharmacotherapy for the treatment of variceal bleeding.
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Affiliation(s)
- R D Grose
- Department of Medicine, Royal Infirmary, Edinburgh, UK
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44
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Shields R, Jenkins SA, Baxter JN, Kingsnorth AN, Ellenbogen S, Makin CA, Gilmore I, Morris AI, Ashby D, West CR. A prospective randomised controlled trial comparing the efficacy of somatostatin with injection sclerotherapy in the control of bleeding oesophageal varices. J Hepatol 1992; 16:128-37. [PMID: 1362432 DOI: 10.1016/s0168-8278(05)80105-9] [Citation(s) in RCA: 84] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Since previous reports have suggested that somatostatin may be of value in the control of acute variceal haemorrhage, we compared its efficacy with that of injection sclerotherapy in a randomised controlled clinical trial. Eighty consecutive patients with endoscopically-proven severe variceal bleeding were randomised to injection sclerotherapy (n = 41) or somatostatin (n = 39) given as a continuous infusion of 250 micrograms/h for 5 days plus daily bolus administration of 250 micrograms. The efficacy of injection sclerotherapy and somatostatin infusion in controlling haemorrhage and preventing rebleeding (censored at 5 days), mortality (censored at 28 days) and complications was compared. The aetiology of the portal hypertension and transfusion requirements was similar between the two groups, but there were more patients with severe liver disease (Child's C) in the somatostatin group. There was no significant difference between the two treatments in the initial (p = 1.0) or overall control of bleeding (p = 0.58). Furthermore, somatostatin was as effective as injection sclerotherapy in controlling bleeding in patients with severe liver disease or in those actively bleeding at the time of their endoscopy. The relative risk of rebleeding whilst receiving somatostatin compared to injection sclerotherapy was 1.39 [95% Confidence Interval (CI) 3.73; 0.52], but this was reduced to 0.98 (95% CI 0.37; 2.67) when readjusted for Child's grading, the only prognostic factor shown to be of significance. Mortality was not significantly different between the two groups of patients (p = 0.31). The relative risk of dying whilst receiving somatostatin compared to injection sclerotherapy was 1.6 (95% CI 3.93; 0.66) but was reduced to 1.03 (95% CI 0.47; 2.47) when adjusted for Child's grading, the only significant prognostic factor. Complications in the somatostatin group were minor and less frequent than after injection sclerotherapy. The results of this study indicate that somatostatin is a safe treatment, which is as effective an endoscopic injection sclerotherapy for acute variceal bleeding.
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Affiliation(s)
- R Shields
- Department of Surgery, Royal Liverpool Hospital, United Kingdom
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45
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Aramaki T, Sekiyama T, Katsuta Y, Kurokawa H, Komeichi H, Tsutsui H, Terada H, Ohsuga M, Satomura K, Okumura H. Long-term haemodynamic effects of a 4-week regimen of nipradilol, a new beta-blocker with nitrovasodilating properties, in patients with portal hypertension due to cirrhosis. A comparative study with propranolol. J Hepatol 1992; 15:48-53. [PMID: 1354676 DOI: 10.1016/0168-8278(92)90010-m] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
To study the long-term effects of pharmacological combination therapy, a comparison was made of the haemodynamic changes in patients with cirrhosis and portal hypertension following a 4-week treatment of propranolol or nipradilol, a new nonselective beta-blocker with nitrovasodilating effect. Nipradilol (12 mg/dag, n = 12) significantly diminished wedged hepatic venous pressure (WHVP, 25 +/- 16%), the hepatic venous pressure gradient (HVPG, 20 +/- 12%), and estimated hepatic blood flow (EHBF, 18 +/- 16%). Propranolol (30 mg/day, n = 11) also caused a significant reduction in WHVP (22 +/- 21%) and HVPG (24 +/- 21%), but not in EHBF. The percentage of portal pressure reduction and the frequency of nonresponders did not differ between the nipradilol and propranolol groups. Both agents reduced heart rate by approx. 20%. Nipradilol, however, did not cause a significant reduction in cardiac index (CI) versus a 14% reduction by propranolol. Pulmonary capillary wedge pressure and central venous pressure, an index of preload, were decreased slightly in the nipradilol group. When nonresponders were excluded, there was a significant correlation of the percentage of reduction between WHVP and CI or systemic vascular resistance, in the nipradilol group. These results indicate that nipradilol may have potent hypotensive effects on portal hypertension, similar but not superior to propranolol. Nipradilol, at the dosage used in the present study, did not appear to exert a nitrovasodilating effect to enhance the portal pressure reduction induced by beta-blocking action.
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Affiliation(s)
- T Aramaki
- First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
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46
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Affiliation(s)
- B R MacDougall
- Institute of Liver Studies, King's College School of Medicine and Dentistry, London
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47
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Abstract
Variceal bleeding has a high mortality, as the majority of patients have cirrhosis, with hepatic coma, renal failure, ascites and clotting deficiencies as complicating factors. Bleeding varices must therefore be treated as an emergency. Resuscitation, endoscopic diagnosis and haemostasis are the cornerstones of treatment. Once bleeding varices have been identified, attempts to stop the bleeding must be made at once as this will lessen the chances of hepatic failure developing. Endoscopic sclerotherapy at the time of diagnosis is the best available treatment at present, although profusely bleeding varices can be difficult to see and inject. In these circumstances the passage of a Sengstaken tube should stop the bleeding, allowing later sclerotherapy to be successful. If rebleeding recurs and cannot be controlled, oesophageal transection with a stapling gun may be life-saving, although the varices may later recur and long-term endoscopic follow-up will be necessary. Portacaval shunting and the distal splenorenal shunt involve arduous surgery and are followed by a significant incidence of hepatic encephalopathy; they should be reserved for those few cases when simpler measures have failed, although shunts do lead to permanent decompression of the portal system. The acute variceal bleed may also be dealt with pharmacologically. Vasopressin, used in combination with nitroglycerin to lessen the harmful side-effects, is cheaper and as effective as terlipressin or somatostatin and its synthetic analogue octreotide. Several courses of injection sclerotherapy will be required to eliminate oesophageal varices. Thereafter, long-term follow-up will be necessary to deal with any recurrence. The place of non-selective beta-blockers is still contentious, but they do reduce portal pressure and may lessen the chance of rebleeding. There is also a growing role for hepatic transplantation, which not only eliminates the varices but also restores liver function to normal and greatly reduces the risk of subsequent hepatoma development.
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48
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Söderlund C, Eriksson LS. Medical and surgical treatment of acute bleeding from esophageal varices in patients with cirrhosis. Scand J Gastroenterol 1991; 26:897-908. [PMID: 1682993 DOI: 10.3109/00365529108996240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- C Söderlund
- Dept. of Surgery, South Hospital, Stockholm, Sweden
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49
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Ruiz del Arbol L, García-Pagán JC, Feu F, Pizcueta MP, Bosch J, Rodés J. Effects of molsidomine, a long acting venous dilator, on portal hypertension. A hemodynamic study in patients with cirrhosis. J Hepatol 1991; 13:179-86. [PMID: 1744422 DOI: 10.1016/0168-8278(91)90812-p] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The present study investigated the effects of molsidomine, a predominant venous dilator which, contrary to organic nitrates, does not produce pharmacological tolerance on splanchnic and systemic hemodynamics in patients with cirrhosis. Twenty-seven cirrhotic portal hypertensive patients were studied prior to and up to 2 h after the oral administration of 2 mg of molsidomine (n = 11), 4 mg of molsidomine (n = 8) or placebo (n = 8). Molsidomine caused a significant reduction in the hepatic venous pressure gradient. The mean decrease at 60 min was -6.8 +/- 9% after 2 mg (p less than 0.05) and -15.4 +/- 12% after 4 mg (p less than 0.01). The decrease in the hepatic venous pressure gradient was maintained at 120 min: -11% after 2 mg (p less than 0.05) and -19% with 4 mg (p less than 0.01). This was associated with mild changes in azygos blood flow and with a significant decrease in hepatic blood flow (-17%, p less than 0.05). There was a moderate reduction in mean arterial pressure (-12.6% after 2 mg and -13.2% after 4 mg, p less than 0.01), which was due to a reduction in cardiac output, without any significant fall in systemic vascular resistance. Placebo administration did not change systemic or hepatic hemodynamics. This study shows that molsidomine causes a significant and sustained reduction in portal pressure in patients with cirrhosis, suggesting the potential role of this agent in the treatment of portal hypertension.
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Affiliation(s)
- L Ruiz del Arbol
- Hepatic Hemodynamics Laboratory, Hospital Clinic i Provincial, University of Barcelona, Spain
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50
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Affiliation(s)
- A K Burroughs
- Hepato-Biliary and Liver Transplantation Unit, Royal Free Hospital, London, United Kingdom
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