pituitrin and Liver-Cirrhosis

Vasoactive agents with endoscopic therapy are used to treat acute variceal bleeding (AVB). There are two main groups of vasoactive agents: terlipressin and vasopressin (T-V), and octreotide and somatostatin (O-S). However, the benefit/harm balance is unclear. Our aim was to assess the efficacy and safety of T-V versus O-S for the management of AVB.. We performed a systematic search for randomized controlled trials (RCTs) in PubMed, Scopus, and CENTRAL. Our main outcomes were mortality and adverse events. Secondary outcomes were bleeding control, rebleeding, blood transfusion, hospital stay. We evaluated the certainty of evidence using GRADE methodology.. We included 21 RCTs. The risk of mortality (RR: 1.01; 95%CI: 0.83-1.22), bleeding control (RR: 0.96; 95%CI: 0.91-1.02; I 2 =53%), early rebleeding (RR: 0.91; 95%CI: 0.66-1.24: I 2 =0%), late rebleeding (RR: 0.94; 95 CI: 0.56-1.60; I 2 =0%), blood transfusion (MD: 0.04; 95%CI: -0.31-0.39; I 2 =68%) and hospital stay (MD: -1.06; 95%CI: -2.80-0.69; I 2 =0%) were similar between T-V and O-S groups. Only 15 studies reported adverse events, which were significantly higher in the T-V compared to the O-S group (RR 2.39; 95%CI: 1.58-3.63; I 2 =57%). The certainty of evidence was moderate for the main outcomes, and low or very low for others.. In cirrhotic patients with AVB, those treated with T-V had similar mortality risk compared to O-S. However, the use of T-V showed an increased risk of adverse events compared to O-S.

Topics: Adult; Aged; Blood Transfusion; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Length of Stay; Liver Cirrhosis; Male; Middle Aged; Octreotide; Recurrence; Somatostatin; Terlipressin; Treatment Outcome; Vasopressins

Approximately 40% to 95% of people with liver cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed within about one to three years after diagnosis. Several different treatments are available, including, among others, endoscopic sclerotherapy, variceal band ligation, somatostatin analogues, vasopressin analogues, and balloon tamponade. However, there is uncertainty surrounding the individual and relative benefits and harms of these treatments.. To compare the benefits and harms of different initial treatments for variceal bleeding from oesophageal varices in adults with decompensated liver cirrhosis, through a network meta-analysis; and to generate rankings of the different treatments for acute bleeding oesophageal varices, according to their benefits and harms.. We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until 17 December 2019, to identify randomised clinical trials (RCTs) in people with cirrhosis and acute bleeding from oesophageal varices.. We included only RCTs (irrespective of language, blinding, or status) in adults with cirrhosis and acutely bleeding oesophageal varices. We excluded RCTs in which participants had bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those in whom initial haemostasis was achieved before inclusion into the trial, and those who had previously undergone liver transplantation.. We performed a network meta-analysis with OpenBUGS software, using Bayesian methods, and calculated the differences in treatments using odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. We performed also the direct comparisons from RCTs using the same codes and the same technical details.. We included a total of 52 RCTs (4580 participants) in the review. Forty-eight trials (4042 participants) were included in one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those with and without a previous history of bleeding. We included outcomes assessed up to six weeks. All trials were at high risk of bias. A total of 19 interventions were compared in the trials (sclerotherapy, somatostatin analogues, vasopressin analogues, sclerotherapy plus somatostatin analogues, variceal band ligation, balloon tamponade, somatostatin analogues plus variceal band ligation, nitrates plus vasopressin analogues, no active intervention, sclerotherapy plus variceal band ligation, balloon tamponade plus sclerotherapy, balloon tamponade plus somatostatin analogues, balloon tamponade plus vasopressin analogues, variceal band ligation plus vasopressin analogues, balloon tamponade plus nitrates plus vasopressin analogues, balloon tamponade plus variceal band ligation, portocaval shunt, sclerotherapy plus transjugular intrahepatic portosystemic shunt (TIPS), and sclerotherapy plus vasopressin analogues). We have reported the effect estimates for the primary and secondary outcomes when there was evidence of differences between the interventions against the reference treatment of sclerotherapy, but reported the other results of the primary and secondary outcomes versus the reference treatment of sclerotherapy without the effect estimates when there was no evidence of differences in order to provide a concise summary of the results. Overall, 15.8% of the trial participants who received the reference treatment of sclerotherapy (chosen because this was the commonest treatment compared in the trials) died during the follow-up periods, which ranged from three days to six weeks. Based on moderate-certainty evidence, somatostatin analogues alone had higher mortality than sclerotherapy (OR 1.57, 95% CrI 1.04 to 2.41; network estimate; direct comparison: 4 trials; 353 participants) and vasopressin analogues alone had higher mortality than sclerotherapy (OR 1.70, 95% CrI 1.13 to 2.62; network estimate; direct comparison: 2 trials; 438 participants). None of the trials reported health-related quality of life. Based on low-certainty evidence, a higher proportion of people receiving balloon tamponade plus sclerotherapy had more serious adverse events than those receiving only sclerotherapy (OR 4.23, 95. 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.

Topics: Adult; Bayes Theorem; Bias; Combined Modality Therapy; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Ligation; Liver Cirrhosis; Network Meta-Analysis; Nitrates; Odds Ratio; Portasystemic Shunt, Transjugular Intrahepatic; Randomized Controlled Trials as Topic; Sclerotherapy; Somatostatin; Vasopressins

Hyponatremia is frequently seen in patients with ascites secondary to advanced cirrhosis and portal hypertension. Although not apparent in the early stages of cirrhosis, the progression of cirrhosis and portal hypertension leads to splanchnic vasodilation, and this leads to the activation of compensatory mechanisms such as renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and antidiuretic hormone (ADH) to ameliorate low circulatory volume. The net effect is the avid retention of sodium and water to compensate for the low effective circulatory volume, resulting in the development of ascites. These compensatory mechanisms lead to impairment of the kidneys to eliminate solute-free water in decompensated cirrhosis. Nonosmotic secretion of antidiuretic hormone (ADH), also known as arginine vasopressin, further worsens excess water retention and thereby hyponatremia. The management of hyponatremia in this setting is a challenge as conventional therapies for hyponatremia including fluid restriction and correction of hypokalemia are frequently inefficacious. In this review, we discuss the pathophysiology, complications, and various treatment modalities, including albumin infusion, selective vasopressin receptor antagonists, or hypertonic saline for patients with severe hyponatremia and those awaiting liver transplantation.

Topics: Acute Kidney Injury; Acute-On-Chronic Liver Failure; Albumins; Antidiuretic Hormone Receptor Antagonists; Ascites; Fluid Therapy; Hepatic Encephalopathy; Hepatorenal Syndrome; Humans; Hypertension, Portal; Hyponatremia; Liver Cirrhosis; Liver Transplantation; Renin-Angiotensin System; Saline Solution, Hypertonic; Splanchnic Circulation; Tolvaptan; Vasodilation; Vasopressins

Hyponatremia is a frequent complication in patients with advanced cirrhosis. Patients with cirrhosis can develop two types of hyponatremia, hypovolemic or hypervolemic (dilutional) hyponatremia. Hypervolemic hyponatremia is the most common type and it develops as a consequence of an impairment in the renal capacity to eliminate solute-free water. The key mechanism leading to solute-free water retention is a non-osmotic hypersecretion of vasopressin (AVP), secondary to a reduction in effective arterial blood pressure existing in patients with advanced cirrhosis. Hypervolemic hyponatremia is associated with increased morbidity and mortality in patients with cirrhosis, and it has also been associated with increased complications after liver transplantation. Currently, the management of hypervolemic hyponatremia in cirrhosis is based on fluid restriction. Vaptans, oral selective vasopressin V2-receptor antagonists, and particularly tolvaptan, have been investigated as a pharmacological approach for the management of hypervolemic hyponatremia in cirrhosis. However, existing information on its efficacy in cirrhosis is still scarce and a recent warning has been raised about their potential role on inducing liver injury at high doses.

Topics: Antidiuretic Hormone Receptor Antagonists; Humans; Hyponatremia; Liver Cirrhosis; Vasopressins

Topics: Antidiuretic Hormone Receptor Antagonists; Aquaporin 2; Ascites; Benzazepines; Diuretics; Humans; Japan; Liver Cirrhosis; Practice Guidelines as Topic; Receptors, Vasopressin; Signal Transduction; Sodium Potassium Chloride Symporter Inhibitors; Spironolactone; Tolvaptan; Vasopressins

Liver cirrhosis is a major cause of morbidity and mortality worldwide, mainly due to complications of portal hypertension. In this article, we review the current understanding on the pathophysiology, the diagnostic criteria and the available therapeutic options for patients with emerging hepatic syndromes in cirrhosis, namely the hepatorenal, hepato-adrenal and hepatopulmonary syndrome. The hepatorenal syndrome is a well-recognized complication of advanced cirrhosis and is usually associated with an accelerated course to death unless liver transplantation is performed. The hepatopulmonary syndrome is often missed in the evaluation of patients with cirrhosis; however, early recognition is essential for the efficient management of individual patients. The hepato-adrenal syndrome, although not fully characterized, offers an exciting field for research and potential therapeutic interventions.

Topics: Acute Kidney Injury; Adrenal Insufficiency; Ascites; Creatinine; Evidence-Based Medicine; Hepatorenal Syndrome; Humans; Hypertension, Portal; Liver Cirrhosis; Liver Transplantation; Lypressin; Midodrine; Norepinephrine; Octreotide; Plasma Substitutes; Portasystemic Shunt, Transjugular Intrahepatic; Serum Albumin; Terlipressin; Vasodilator Agents; Vasopressins

Arginine-vasopressin (AVP) is an important hormone in the regulation of plasma osmolality and blood volume/pressure. In clinical practice it is frequently used in the treatment of septic shock and decompensated cirrhosis. In this review the physiology of AVP and its analogues is presented. In addition the use of AVP in cirrhosis and sepsis is reviewed.

Topics: Arginine Vasopressin; Humans; Liver Circulation; Liver Cirrhosis; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vasopressins

Kidney dysfunction is a common complication of patients with advanced cirrhosis and is associated with poor prognosis. Patients with advanced cirrhosis show circulatory dysfunction characterized by reduced systemic vascular resistance due to splanchnic arterial vasodilation, which is caused by portal hypertension. The progressive reduction in systemic vascular resistance leads to effective arterial hypovolemia. In order to maintain arterial pressure within normal limits in this setting, there is activation of systemic vasoconstrictor systems, including the renin-angiotensin-aldosterone system, sympathetic nervous system and, in late stages, nonosmotic hypersecretion of vasopressin. Although these systems have positive effects in maintaining arterial pressure, they have a negative influence on kidney function, leading to the retention of sodium and solute-free water, and in late stages of the disease an intense kidney vasoconstriction develops, leading to decrease of the glomerular filtration rate and the development of hepatorenal syndrome (HRS). Moreover, bacterial translocation and the existence of a systemic inflammatory state in patients with advanced cirrhosis may play a role in the impairment of circulatory function. HRS is a unique cause of kidney failure of functional origin that develops in patients with cirrhosis. However, besides HRS, patients with cirrhosis may develop kidney failure due to other causes, including bacterial infections, prerenal kidney failure, shock, use of nephrotoxic drugs or intrinsic kidney diseases. Considering the existence of circulatory dysfunction and some degree of kidney vasoconstriction, patients with advanced cirrhosis have fragile kidney function and are susceptible to easily developing kidney failure associated with other complications of the disease, particularly bacterial infections and gastrointestinal bleeding.

Topics: Hemodynamics; Hepatorenal Syndrome; Humans; Hypertension, Portal; Hypovolemia; Inflammation; Kidney; Liver; Liver Circulation; Liver Cirrhosis; Vascular Resistance; Vasopressins

Cirrhosis is characterized by systemic and splanchnic vasodilation that leads to excessive nonosmotic secretion of vasopressin (antidiuretic hormone). Hyponatremia is a common electrolyte abnormality in advanced liver disease that results from the impaired ability of the kidney to excrete solute-free water that leads to "dilutional" hyponatremia-water retention disproportionate to the retention of sodium. Hyponatremia in liver diseases carries the prognostic burden, correlates with the severity of cirrhosis, and, in recent studies, has also been implicated in the pathogenesis of hepatic encephalopathy. The current treatment options are limited to conventional therapies like fluid restriction, and the outcomes are unsatisfactory. Although currently available vasopressin (V2 receptors) antagonists have been shown to increase serum sodium concentrations and improve ascites control, their role in the treatment of hyponatremia in liver disease patients remains questionable because of adverse effect profiles, high cost, and poor data on long-term mortality benefits. More information is needed to argue the benefits vs risks of short-term use of vaptans for correction of hyponatremia especially just hours-to-days before liver transplant.

Topics: Drug Therapy, Combination; Female; Humans; Hyponatremia; Liver Cirrhosis; Male; Prognosis; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome; Vasopressins

Hyponatremia is a frequent complication of advanced cirrhosis with ascites associated with increased morbidity and mortality. It is caused by an impairment in the renal capacity to eliminate solute-free water and is considered to be related to persistent secretion of vasopressin despite low serum osmolality. This nonosmotic release of vasopressin is mediated by the autonomic nervous system, which senses the underfilling of arterial vascular component. This reduction of effective arterial blood volume is closely related to the development of ascites. Although the short-time effects of vasopressin V2 receptor antagonists (vaptans) on hyponatremia and ascites have been repeatedly reported, their effects on the long-term management of cirrhotic ascites have not been established yet. Considering that their effects on water diuresis and their safety are limited by severe underfilling state of patients, cautious approaches with adequate monitoring are needed to advanced cirrhosis. Proper indication, adequate doses and new possibility of combination therapy should be explored in the future controlled study. As hyponatremia is frequent obstacle to ascites management, judicious combination with low-dose diuretics may decrease the incidence of refractory ascites. Although vaptans show much promise in the treatment of advanced cirrhosis, the problem of high cost should be solved for the future.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Aquaporin 2; Ascites; Biomarkers; Humans; Liver Cirrhosis; Neurophysins; Patient Selection; Protein Precursors; Receptors, Vasopressin; Risk Factors; Treatment Outcome; Vasopressins; Water-Electrolyte Balance

Acute kidney injury (AKI) is frequent in patients with cirrhosis. AKI and hyponatraemia are major determinants of the poor prognosis in advanced cirrhosis. The hepatorenal syndrome (HRS) denotes a functional and potential reversible impairment of renal function. Type 1 HRS, a special type of AKI, is a rapidly progressive AKI, whereas the renal function in type 2 HRS decreases more slowly. HRS is precipitated by factors such as sepsis that aggravate the effective hypovolaemia in decompensated cirrhosis, by lowering arterial pressure and cardiac output and enhanced sympathetic nervous activity. Therefore, attempts to prevent and treat HRS should seek to improve liver function and to ameliorate arterial hypotension, central hypovolaemia and cardiac output, and to reduce renal vasoconstriction. Ample treatment of HRS is important to prevent further progression and death, but as medical treatment only modestly improves long-term survival, these patients should always be considered for liver transplantation. Hyponatraemia, defined as serum sodium <130 mmol/L, is common in patients with decompensated cirrhosis. From a pathophysiological point of view, hyponatraemia is related to an impairment of renal solute-free water excretion most likely caused by an increased vasopressin secretion. Patients with cirrhosis mainly develop hypervolaemic hyponatraemia. Current evidence does not support routine use of vaptans in the management of hyponatraemia in cirrhosis.

Topics: Cardiomyopathies; Creatinine; Glomerular Filtration Rate; Hepatorenal Syndrome; Humans; Hyponatremia; Liver Cirrhosis; Vasopressins

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.

Topics: Acute Disease; Acute Kidney Injury; Anti-Bacterial Agents; Balloon Occlusion; Blood Transfusion; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hepatic Encephalopathy; Hormones; Humans; Hypertension, Portal; Intubation, Intratracheal; Liver Cirrhosis; Portasystemic Shunt, Transjugular Intrahepatic; Somatostatin; Vasoconstrictor Agents; Vasopressins

Water excretion is regulated in large part through the regulation of osmotic water permeability of the renal collecting duct epithelium. Water permeability is controlled by vasopressin through regulation of the water channel, aquaporin-2 (AQP2). Two processes contribute: (1) regulation of AQP2 trafficking to the apical plasma membrane; and (2) regulation of the total amount of the AQP2 protein in the cells. Regulation of AQP2 abundance is defective in several water-balance disorders, including many polyuric disorders and the syndrome of inappropriate antidiuresis. Here we review vasopressin signaling in the renal collecting duct that is relevant to the two modes of water permeability regulation.

Topics: Animals; Aquaporin 2; beta Catenin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Heart Failure; Humans; Inappropriate ADH Syndrome; Kidney Tubules, Collecting; Liver Cirrhosis; Mice; Myosin-Light-Chain Kinase; Nephrotic Syndrome; Permeability; Phosphoproteins; Phosphorylation; Polyuria; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-jun; Rats; Signal Transduction; Transcription Factor AP-1; Transcription Factors; Vasopressins

Vasopressin and terlipressin, a long-acting V1a analogue, are increasingly used in intensive care. The main clinical indications are the treatment of patients with septic shock and of patients with cirrhosis, who develop variceal bleeding, the hepatorenal syndrome or both. In this review, we summarize the effects of these drugs on splanchnic hemodynamics and organ function.. A recent systematic meta-analysis of randomized trials suggests that terlipressin may improve renal function in hepatorenal syndrome and thereby reduce mortality by 34%. Moreover, a recent study reported that association of terlipressin and albumin was more effective than terlipressin alone. In patients with variceal bleeding, the bleeding control is significantly improved by early administration of terlipressin. The place of vasopressin in the treatment of patients with septic shock is still discussed, but compared with norepinephrine, vasopressin showed at least an equal efficacy.. The use of vasopressin and its synthetic analogues has shown beneficial effects in the management of patients with cirrhosis, especially in the context of variceal bleeding, the hepatorenal syndrome or both. In both cases, the use of terlipressin improved survival. Therefore, in these clinical indications, terlipressin is a part of recommendations. The role of vasopressin in patients with septic shock remains to be precisely evaluated.

Topics: Critical Care; Critical Illness; Hemodynamics; Hepatorenal Syndrome; Humans; Intensive Care Units; Liver; Liver Cirrhosis; Lypressin; Risk Factors; Shock, Septic; Terlipressin; Varicose Veins; Vasoconstrictor Agents; Vasopressins

Emergency sclerotherapy is still widely used as a first line therapy for variceal bleeding in patients with cirrhosis, particularly when banding ligation is not available or feasible. However, pharmacological treatment may stop bleeding in the majority of these patients.. To assess the benefits and harms of emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis.. Search of trials was based on The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded through January 2010.. Randomised clinical trials comparing sclerotherapy with vasoactive drugs (vasopressin (with or without nitroglycerin), terlipressin, somatostatin, or octreotide) for acute variceal bleeding in cirrhotic patients.. Outcome measures were failure to control bleeding, five-day treatment failure, rebleeding, mortality, number of blood transfusions, and adverse events. Data were analysed by a random-effects model according to the vasoactive treatment. Sensitivity analyses included combined analysis of all the trials irrespective of the vasoactive drug, type of publication, and risk of bias.. Seventeen trials including 1817 patients were identified. Vasoactive drugs were vasopressin (one trial), terlipressin (one trial), somatostatin (five trials), and octreotide (ten trials). No significant differences were found comparing sclerotherapy with each vasoactive drug for any outcome. Combining all the trials irrespective of the vasoactive drug, the risk differences (95% confidence intervals) were failure to control bleeding -0.02 (-0.06 to 0.02), five-day failure rate -0.05 (-0.10 to 0.01), rebleeding 0.01 (-0.03 to 0.05), mortality (17 randomised trials, 1817 patients) -0.02 (-0.06 to 0.02), and transfused blood units (8 randomised trials, 849 patients) (weighted mean difference) -0.24 (-0.54 to 0.07). Adverse events 0.08 (0.03 to 0.14) and serious adverse events 0.05 (0.02 to 0.08) were significantly more frequent with sclerotherapy.. We found no convincing evidence to support the use of emergency sclerotherapy for variceal bleeding in cirrhosis as the first, single treatment when compared with vasoactive drugs. Vasoactive drugs may be safe and effective whenever endoscopic therapy is not promptly available and seems to be associated with less adverse events than emergency sclerotherapy. Other meta-analyses and guidelines advocate that combined vasoactive drugs and endoscopic therapy is superior to either intervention alone.

Topics: Emergencies; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostatics; Humans; Liver Cirrhosis; Lypressin; Octreotide; Sclerotherapy; Somatostatin; Terlipressin; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Gastroesophageal variceal hemorrhage is a major complication of portal hypertension in 50% to 60% of patients with liver cirrhosis and is a frequent cause of mortality in these patients. The prevalence of variceal hemorrhage is approximately 5% to 15% yearly, and early variceal rebleeding has a rate of occurrence of 30% to 40% within the first 6 weeks. More than 50% of patients who survive after the first bleeding episode will experience recurrent bleeding within 1 year. Management of gastroesophageal varices should include prevention of initial and recurrent bleeding episodes and control of active hemorrhage. Therapies used in the management of gastroesophageal variceal hemorrhage may include pharmacologic therapy (vasoactive agents, nonselective b-blockers, and antibiotic prophylaxis), endoscopic therapy, transjugular intrahepatic portosystemic shunt, and shunt surgery. This article focuses primarily on pharmacologic management of acute variceal hemorrhage.

Topics: End Stage Liver Disease; Esophageal and Gastric Varices; Gastrointestinal Agents; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Octreotide; Primary Prevention; Prognosis; Proton Pump Inhibitors; Recurrence; Risk Factors; Sclerotherapy; Severity of Illness Index; Vasoconstrictor Agents; Vasopressins

Hyponatremia is the most prevalent electrolyte disorder in hospitalized patients. Vasopressin plays an important role in the pathogenesis of this disorder through its action on the vasopressin type 2 receptor (V(2)R), leading to electrolyte-free water reabsorption. Multiple vasopressin receptor antagonists have recently been developed that differ in their specificity for V(2)R and V(1)R. These agents have applications in diseases that can result in hypervolemic and euvolemic hyponatremia, such as the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure and cirrhosis. V(2)R antagonists have demonstrated promise in the short-term correction of hyponatremia, although the long-term survival benefits of these drugs are less clear. This review discusses the physiology of vasopressin in hyponatremia, the clinical implications of the disorder and examples of individual therapeutics used in treatment strategies.

Topics: Animals; Antidiuretic Agents; Antidiuretic Hormone Receptor Antagonists; Clinical Trials as Topic; Heart Failure; Humans; Hyponatremia; Inappropriate ADH Syndrome; Liver Cirrhosis; Receptors, Vasopressin; Vasopressins

Hyponatremia is the most common electrolyte disorder in patients with cirrhosis. This disorder can be a result of substantial loss of extracellular fluid "hypotonic or hypovolemic hyponatremia" or develop in the context of an increase in extracellular fluid volume and in the absence of major sodium losses; this situation occurs in patients with advanced cirrhosis and is known as "dilutional or hypervolemic hyponatremia". In dilutional or hypervolemic hyponatremia, serum sodium concentration is reduced, plasma volume is increased (although the effective plasma volume is decreased due to marked arterial vasodilation in the splanchnic circulation) and extracellular fluid volume is increased, with ascites and edema in the absence of signs of dehydration. This is a result of the marked deterioration in renal excretion of solute-free water, leading to disproportionate water retention in relation to sodium retention. Hypotonic hyponatremia represents 10% of all hyponatremias in patients with cirrhosis. Since hypervolemic hyponatremia is by far the most frequent form of this disorder, the present chapter will concentrate specifically on hypervolemic hyponatremia in cirrhosis.

Topics: Antidiuretic Hormone Receptor Antagonists; Ascites; Blood Volume; Contraindications; Disease Progression; Diuresis; Extracellular Fluid; Humans; Hyponatremia; Inappropriate ADH Syndrome; Kidney; Liver Cirrhosis; Liver Transplantation; Natriuresis; Prognosis; Saline Solution, Hypertonic; Splanchnic Circulation; Vasodilation; Vasopressins

The non-peptide vasopressin antagonists (VPA), called vaptans, were developed in the 1990s to antagonize both the pressor and antidiuretic effects of vasopressin. There are three subtypes of VPA receptors: V1a, V1b and V2. V1a receptors are widely distributed in the body, mainly the blood vessels and myocardium. The V1b receptors are located mainly in the anterior pituitary gland and play a role in ACTH release. V2 receptors are located in the collecting tubular renal cells. Both V1a and V1b receptors act through the intracellular phosphoinositol signalling pathway, Ca(++) being the second messenger. V2 receptors work through AMPc generation, which promotes aquaporin 2 (AQP2) trafficking and allows water to enter the cell. The vaptans act competitively at the AVP receptor. The most important are mozavaptan, lixivaptan, satavaptan and tolvaptan, all of which are selective V2 antagonists and are administered through the oral route. In contrast, conivaptan is a dual V1 and V2 antagonist administered through the endovenous route. The main characteristics of vaptans are their effect on free water elimination without affecting electrolyte excretion. There are several studies on the effects of these drugs in hypervolemic hyponatremia (heart failure, hepatic cirrhosis) as well as in normovolemic hyponatremia (inappropriate secretion of ADH [SIADH]). Current studies show that the vaptans are effective and well tolerated, although knowledge of these drugs remains limited. There are no studies of the use of vaptans in severe hyponatremia. Osmotic demyelination syndrome due to excessively rapid correction of hyponatremia has not been described.

Topics: Adult; Antidiuretic Hormone Receptor Antagonists; Aquaporin 2; Benzamides; Benzazepines; Calcium Signaling; Clinical Trials as Topic; Cyclic AMP; Double-Blind Method; Drug Therapy, Combination; Heart Failure; Humans; Hyponatremia; Inappropriate ADH Syndrome; Kidney Tubules, Collecting; Liver Cirrhosis; Morpholines; Multicenter Studies as Topic; Neoplasms; Pituitary Gland, Anterior; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vasopressin; Second Messenger Systems; Spiro Compounds; Tolvaptan; Vasopressins

The hepatorenal syndrome (HRS) is an acute functional renal failure due to renal arterial vasoconstriction occurring in cirrhotic patients with vascular dysfunction. The renal arterial vasoconstriction is the result of diffuse arteriole vasodilatation. There are two types of HRS, which can be differentiated according to the course and the stage of the renal failure; they have a different prognosis. Liver transplantation remains the standard treatment. Maintenance medical therapy is mainly based on vasopressin analogues. The interest of both dialysis and portosystemic intrahepatic shunt techniques remains to be determined. The prognosis of HRS is poor and in the absence of treatment, onset is usually followed by rapid fatal outcome.

Topics: Combined Modality Therapy; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Liver Transplantation; Models, Biological; Prognosis; Renal Replacement Therapy; Vasoconstriction; Vasodilator Agents; Vasopressins

Topics: Animals; Aquaporin 2; Aquaporins; Endocytosis; Exocytosis; Heart Failure; Humans; Kidney; Kidney Concentrating Ability; Liver Cirrhosis; Phosphorylation; Protein Transport; Signal Transduction; Urologic Diseases; Vasopressins; Water; Water-Electrolyte Balance; Water-Electrolyte Imbalance

The hepatorenal syndrome (HRS) is a common complication in advanced liver cirrhosis, and often occurs in patients with ascites and severe circulatory dysfunction. HRS is a functional renal failure which was believed to be the end result of progressive splanchnic vasodilatation. However, recent data have implicated a role of reduced cardiac output as well as endothelial dysfunction in the etiology of HRS. Type 1 HRS is associated with a poor prognosis and often occurs in conjunction with microcirculatory dysfunction in other organs, including the heart, brain and liver. The treatment of type 1 HRS has centered around vasoconstrictors and intravenous hydration, traditionally midodrine and albumin. However, new vasoconstrictors (specifically vasopressin analogues), transjugular intrahepatic portacaval shunts, and albumin dialysis have been introduced as potential therapies. This review will discuss new advances in the diagnosis and pathogenesis of HRS, with an emphasis on the management.

Topics: Albumins; Drug Therapy, Combination; Evidence-Based Medicine; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Liver Transplantation; Midodrine; Norepinephrine; Portacaval Shunt, Surgical; Prognosis; Renal Dialysis; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

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.

Topics: Algorithms; Endoscopy, Gastrointestinal; Esophageal and Gastric Varices; Gastrointestinal Agents; Gastrointestinal Hemorrhage; Hemodynamics; Humans; Hypertension, Portal; Liver Cirrhosis; Octreotide; Portal System; Primary Prevention; Secondary Prevention; Vasoconstrictor Agents; Vasopressins

Bleeding of oesophageal varices and hepatorenal syndrome are most dramatic complications in gastroenterology. They develop in consequence of progressively increasing blood flow entering the vasodilated splanchnic bed and the portal vein where blood flow meets intrahepatic resistance. Porto-systemic collateral veins are formed to bypass the cirrhotic liver. Intravascular pressure is very high in these collaterals, causing the venous walls to expand into esophageal varices, which eventually may rupture and bleed. This splanchnic blood pooling generates hypovolemia in the central and arterial system, initiating activation of the renin-angiotensin-aldosteron and sympathetic nervous system. These compensatory mechanisms induce renal vasoconstriction, followed by hypoperfusion of the kidneys and development of hepatorenal syndrome. Vasoconstrictors like terlipressin inhibit splanchnic blood flow, thus reducing portal and variceal pressure, which is followed by termination ofvariceal bleeding, by normalization of central and arterial blood volume and by an improvement of kidney function and hepatorenal syndrome.

Topics: Animals; Blood Circulation; Gastrointestinal Hemorrhage; Hepatorenal Syndrome; Humans; Hypovolemia; Liver Cirrhosis; Lypressin; Splanchnic Circulation; Terlipressin; Vasoconstrictor Agents; Vasopressins

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.

Topics: Acute Disease; Adrenergic beta-Antagonists; Antibiotic Prophylaxis; Drug Therapy, Combination; Esophageal and Gastric Varices; Humans; Hypertension, Portal; Liver Cirrhosis; Lypressin; Octreotide; Somatostatin; Terlipressin; Vasoconstrictor Agents; Vasopressins

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.

Topics: Adrenergic beta-Antagonists; Algorithms; Antihypertensive Agents; Cardiovascular Agents; Esophageal and Gastric Varices; Esophagoscopy; Gastrointestinal Hemorrhage; Hemostatics; Humans; Hypertension, Portal; Ligation; Liver Cirrhosis; Nitrates; Portasystemic Shunt, Transjugular Intrahepatic; Recurrence; Sclerotherapy; Somatostatin; Vasoconstrictor Agents; Vasopressins

Portal hypertension is one of the main consequences of cirrhosis. It results from a combination of increased intrahepatic vascular resistance and increased blood flow through the portal venous system. The condition leads to the formation of portosystemic collateral veins. Esophagogastric varices have the greatest clinical impact, with a risk of bleeding as high as 30% within 2 years of medium or large varices developing. Ascites, another important complication of advanced cirrhosis and severe portal hypertension, is sometimes refractory to treatment and is complicated by spontaneous bacterial peritonitis and hepatorenal syndrome. We describe the pathophysiology of portal hypertension and the current management of its complications, with emphasis on the prophylaxis and treatment of variceal bleeding and ascites.

Topics: Algorithms; Anti-Bacterial Agents; Ascites; Collateral Circulation; Diuretics; Endoscopy, Gastrointestinal; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hepatorenal Syndrome; Hormones; Hypertension, Portal; Liver Cirrhosis; Lypressin; Peritonitis; Portasystemic Shunt, Transjugular Intrahepatic; Sclerotherapy; Secondary Prevention; Somatostatin; Spironolactone; Terlipressin; Vascular Resistance; Vasoconstrictor Agents; Vasodilation; Vasopressins

This article discusses the pathophysiology of sodium and water retention in edematous disorders with a particular focus on cardiac failure, cirrhosis, and pregnancy. The body fluid volume hypothesis, which emphasizes the dominant role of arterial baroreceptors in renal sodium and water excretion, is reviewed. With arterial underfilling, either due to a decrease in cardiac output or peripheral arterial vasodilation, the normal central inhibition of the sympathetic nervous system activity and baroreceptor-mediated, nonosmotic arginine vasopressin (AVP) release is attenuated. The resultant increase in renal adrenergic activity stimulates the renin-angiotensin-aldosterone system. Although the resultant increase in systemic vascular resistance compensates for the primary arterial underfilling, this activation of the neurohumoral axis results in diminished sodium and water delivery to the renal collecting duct sites of aldosterone, AVP, and natriuretic peptide action. This diminished distal sodium and water delivery will be discussed as an important factor in the failure to escape from the sodium-retaining effects of aldosterone, the resistance to the natriuretic and diuretic effects of natriuretic peptides, and the diminished maximal solute-free water excretion in patients with edema. The role of the nonosmotic AVP release in water retention and hypo-osmolality/hyponatremia has been demonstrated in patients and experimental animals by administering nonpeptide, orally active vasopressin V2 receptor antagonists. These agents have been found to increase solute-free water excretion in patients with water-retaining, hyponatremic edema as well as in experimental animals.

Topics: Aldosterone; Body Water; Edema; Female; Heart Failure; Humans; Hyponatremia; Liver Cirrhosis; Pregnancy; Pregnancy Complications; Renin-Angiotensin System; Vasodilation; Vasopressins

Hepatorenal syndrome is a severe, but not uncommon complication of decompensated liver cirrhosis. In particular, the rapidly progressive form of hepatorenal syndrome (type 1) is associated with a dismal prognosis. Established hepatorenal syndrome has a spontaneous reversibility below 5%. Hepatorenal syndrome is involved in more than 50% of cirrhosis-related mortality. Thus, any treatment capable of reversing hepatorenal syndrome would be expected to reduce morbidity and mortality from liver cirrhosis. A pathophysiological hallmark of hepatorenal syndrome is arterial underfilling due to an extreme splanchnic vasodilatation. Consequently, potent vasoconstrictors capable of reversing this vasodilatation have been investigated in hepatorenal syndrome. Several vasoconstrictors including the alpha-adrenergic agonists, midodrine and noradrenalin, and the vasopressor analogues, ornipressin and terlipressin, have all been associated with a significant improvement in renal function in 57 to 100% of cases and even reversal of hepatorenal syndrome in 42 to 100% of cases. The majority of recent studies are on terlipressin. A randomized, controlled trial showed a significant effect of terlipressin on reversal of hepatorenal syndrome. The contribution of volume expansion to the beneficial effects of vasoconstrictors on hepatorenal syndrome remains to be determined. In general, reversal of hepatorenal syndrome was associated with an improved survival. However, it remains to be determined if vasoconstrictor therapy should be used in hepatorenal syndrome in general, or if it should be reserved for potential candidates for liver transplantation. In conclusion, evidence for a beneficial effect of vasoconstrictor therapy for the treatment of hepatorenal syndrome is steadily accumulating. Confirmation of the preliminary data in larger randomized, controlled trials looking at long-term survival is required.

Topics: Adrenergic alpha-Agonists; Animals; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Randomized Controlled Trials as Topic; Splanchnic Circulation; Vasoconstrictor Agents; Vasopressins

Topics: Hepatorenal Syndrome; Humans; Kidney; Liver Cirrhosis; Liver Transplantation; Preoperative Care; Treatment Outcome; Vasoconstrictor Agents; Vasopressins

Topics: Humans; Inappropriate ADH Syndrome; Liver Cirrhosis; Vasopressins

A POTENTIALLY SEVERE EVENT: Upper gastrointestinal haemorrhage in a cirrhotic patient is always extremely serious, particularly in the case of rupture of the oesophageal varices, which is the most frequent cause. THE TWO POLES OF TREATMENT: Early vasoactive treatment permits elastic ligature in optimal conditions using an endoscope. The prevention of other complications of cirrhosis is an essential element in the management of these patients.

Topics: Acute Disease; Emergencies; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostasis, Endoscopic; Hemostatics; Hepatic Encephalopathy; Hormones; Humans; Hypertension, Portal; Ligation; Liver Cirrhosis; Octreotide; Recurrence; Risk Factors; Rupture; Sclerotherapy; Shock, Hemorrhagic; Somatostatin; Vasopressins

Vasopressin, or antidiuretic hormone, is a peptide hormone that is released from the posterior pituitary gland in response to changes in blood pressure and plasma osmolality. The main pathophysiological states associated with high plasma vasopressin concentrations are cirrhosis, cardiac failure and syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Pharmacological treatments for disorders of excess vasopressin secretion have been limited. However, oral bio-available selective and non-selective V(1) and V(2) receptor antagonists have recently become available for clinical use. Water retention in cirrhosis is a common problem, leading to ascites, peripheral oedema and hyponatraemia. Raised plasma vasopressin concentrations and decreased delivery of glomerular filtrate are believed to be the most important factors in the development of water retention. V(2) receptor antagonists are aquaretic agents that promote water excretion and improve hyponatraemia. Their potential role in cirrhosis has been examined in a number of recent studies that have shown increased free water clearance and serum sodium concentrations with few adverse effects. V(2) receptor antagonists represent a novel and promising new class of agent that may have major clinical utility in the treatment of patients with liver cirrhosis.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Controlled Clinical Trials as Topic; Diuretics; Heart Failure; Homeostasis; Humans; Inappropriate ADH Syndrome; Liver Cirrhosis; Models, Animal; Morpholines; Piperidines; Pyrroles; Quinolones; Rats; Spiro Compounds; Vasopressins

Emergency sclerotherapy is used as a first-line therapy for variceal bleeding in cirrhosis, although pharmacologic treatment stops bleeding in most patients. We performed a meta-analysis comparing emergency sclerotherapy with pharmacologic treatment.. MEDLINE (1968-2002), EMBASE (1986-2002), and the Cochrane Library (2002;4) were searched to retrieve randomized controlled trials comparing sclerotherapy with vasopressin (+/- nitroglycerin), terlipressin, somatostatin, or octreotide for variceal bleeding in cirrhosis. Outcome measures were failure to control bleeding, rebleeding, blood transfusions, adverse events, and mortality.. Fifteen trials were identified. Sclerotherapy was not superior to terlipressin, somatostatin, or octreotide for any outcome and to vasopressin for rebleeding, blood transfusions, death, and adverse events; it was superior to vasopressin for the control of bleeding in a single trial flawed by a potential detection bias. Sclerotherapy was associated with significantly more adverse events than somatostatin. In a predefined sensitivity analysis, combining all of the trials irrespective of the control treatment, risk differences (sclerotherapy minus control) and confidence intervals (CIs) were as follows: failure to control bleeding, -0.03 (-0.06 to 0.01); mortality, -0.035 (-0.07 to 0.008); adverse events, 0.08 (0.02 to 0.14). Mortality risk difference was -0.01 (-0.07 to 0.04) in good-quality trials and -0.08 (-0.14 to -0.02) in poor-quality trials.. Available evidence does not support emergency sclerotherapy as the first-line treatment of variceal bleeding in cirrhosis when compared with vasoactive drugs, which control bleeding in 83% of patients. Therefore, endoscopic therapy might be added only in pharmacologic treatment failures.

Topics: Acute Disease; Emergency Medical Services; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostatics; Hormones; Humans; Liver Cirrhosis; Lypressin; Octreotide; Randomized Controlled Trials as Topic; Sclerotherapy; Somatostatin; Terlipressin; Vasoconstrictor Agents; Vasopressins

The hepatorenal syndrome is a form of renal failure occurring in patients with advanced liver disease. The diagnosis is based both on the demonstration of low GFR and exclusion of other common causes of renal failure that may occur in patients with cirrhosis. Orthotopic liver transplantation remains the only curative treatment for this poor outcome disease; other modalities such as vasopressin analogues, transjugular intrahepatic portosystemic shunt or renal replacement therapies may serve as a bridge to transplantation. This article reviews the pathophysiology, diagnosis and current treatment of hepatorenal syndrome.

Topics: Acute Kidney Injury; Creatinine; Diagnosis, Differential; Edema; Glomerular Filtration Rate; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Liver Transplantation; Peritoneovenous Shunt; Portasystemic Shunt, Surgical; Renal Circulation; Renal Replacement Therapy; Renin-Angiotensin System; Serum Albumin; Splanchnic Circulation; Vasoconstrictor Agents; Vasodilator Agents; Vasopressins; Water-Electrolyte Imbalance

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Aquaporin 2; Aquaporin 6; Aquaporins; Ascites; Benzeneacetamides; Body Water; Demeclocycline; Diuresis; Diuretics; Humans; Kidney Tubules, Collecting; Liver Cirrhosis; Liver Cirrhosis, Experimental; Morpholines; Pyrrolidines; Rats; Receptors, Opioid, kappa; Receptors, Vasopressin; Spiro Compounds; Vasopressins

The kidneys play the crucial role in the maintenance of the body fluid volume homeostasis. Several hypotheses have been introduced to explain sodium and water retention leading to edematous states in such pathologic conditions as congestive heart failure (CHF) and cirrhosis. We have suggested a unifying arterial underfilling hypothesis, explaining the development of edema in these conditions. Arterial underfilling, caused by decreased cardiac output or peripheral arterial vasodilation, leads to activation of the sympathetic nervous system, renin-angiotensin-aldosterone system, and nonosmotic vasopressin release. This review discusses the pathophysiologic mechanisms resulting in renal sodium and water retention, impaired mineralocorticoid escape, and resistance to atrial natriuretic peptide in patients with CHF and cirrhosis. Furthermore, the basis of current therapies in these disorders is discussed, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, aldosterone antagonists, and diuretics in CHF and cirrhosis, as well as new approaches to treatment of water retention with vasopressin V(2) receptor antagonists.

Topics: Body Water; Heart Failure; Homeostasis; Humans; Liver Cirrhosis; Renin-Angiotensin System; Sodium; Sympathetic Nervous System; Vasopressins

Topics: Azepines; Benzamides; Brain Diseases, Metabolic; Humans; Hyponatremia; Inappropriate ADH Syndrome; Liver Cirrhosis; Pyrroles; Vasopressins

Disorders of the serum sodium concentration (hypo- and hypernatremia) are amongst the most frequent electrolyte disorders in clinical medicine. They are attributable to disturbance of to water metabolism. Hyponatremia is almost always a condition of water excess while hypernatremia is due water deficiency. Physiological normonatremia (normal plasma osmolality) is maintained by an integrated system involving regulated water intake via thirst and control of water excretion via antidiuretic hormone secretion. Therefore hypo- and hypernatremia should be analyzed in terms of dysregulated ADH secretion, fluid intake and renal water excretion. Hyponatremia is usually a disorder of vasopressin excess, due to 'non-osmotic' vasopressin release. The latter may occur in two different settings: (I) SIADH, (II) baroreceptor mediated vasopressin secretion (cardiac failure, liver cirrhosis). This entities are easy to distinguish in clinical practice. SIADH is associated with striking lower plasma concentrations of urate, creatinine and urea. In SIADH the blood pressure is normal and there is no edema. In contrast in the hyponatremia of liver cirrhosis and heart failure the plasma measurements indicated are usually slightly elevated, the blood pressure is low and there is edema. The typical patient with hypernatremia is old and has no thirst sensation. Hypo- or hypernatremia may cause major neurologic symptoms. These symptoms are more related to the rate of change in the serum sodium concentration than to the absolute level of a hypo- or hypernatremia reached. The traditional treatment for hyponatremia used to be water restriction. However V2-Vasopressin-Antagonists may provide a better treatment modality in the future. Hypernatremia is treated by slow rehydratation.

Topics: Diagnosis, Differential; Drinking; Fluid Therapy; Heart Failure; Humans; Hypernatremia; Hyponatremia; Inappropriate ADH Syndrome; Liver Cirrhosis; Vasopressins

The changes in sodium homeostasis most frequently are expression of water-electrolyte balance disturbances in patients with liver cirrhosis. Hyponatremia of water excess is found in 35% of the patients with cirrhosis and ascites. This disturbance is most frequently connected with raised antidiuretic hormone (vasopressin) secretion and is realized by including of nonosmotic stimulating mechanisms. The vasopressin plays a leading role in pathogenesis of disturbed water metabolism in the liver cirrhosis. Some patients with hepatorenal syndrome are established with highest plasma vasopressin concentrations. Gene expression of the regulation of kidney vasopressin-sensitive water channels (aquaporin-2 proteins) is also raised in the liver cirrhosis. Using in practice vasopressin-type 2 (V-2) receptor antagonists gives hopeful results in medical treatment of water-electrolyte disturbances in patients with advanced liver cirrhosis.

Topics: Gene Expression; Humans; Hyponatremia; Liver Cirrhosis; Renal Insufficiency; Sodium; Vasopressins; Water-Electrolyte Imbalance

Topics: Antidiuretic Hormone Receptor Antagonists; Body Water; Humans; Hyponatremia; Kidney; Liver Cirrhosis; Receptors, Vasopressin; Vasopressins

An impairment in the renal capacity to excrete water is a common finding in patients with cirrhosis and ascites. In some patients this abnormality is minor since it is only detectable by measuring urine volume or free water clearance after a water load and is not associated with changes in plasma osmolality and serum sodium concentration. In other patients the intensity of the disorder is such that they are not able to eliminate their regular water intake, and develop dilutional hyponatremia and hypoosmolality. The renal capacity to excrete water is one of the most useful prognostic indicators in patients with cirrhosis and ascites. The main pathogenic factors of the impaired water excretion in human cirrhosis are an increased plasma concentration of AVP, a reduced renal synthesis of prostaglandins and a reduced delivery of filtrate to the ascending limb of the loop of Henle. At present, no effective therapy exists for the management of this complication. Two types of drugs have recently been reported that selectively increase renal water excretion, antagonists of the AVP V2 receptors and kappa-opioid agonists. Experimental studies have shown that both substances improve water excretion in rats with cirrhosis and ascites. Therefore, these drugs may represent a novel therapeutic tool in the management of spontaneous hyponatremia in cirrhosis and in the treatment or prevention of diuretic-induced hyponatremia in these patients.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Diuresis; Diuretics; Humans; Hyponatremia; Liver Cirrhosis; Receptors, Opioid, kappa; Vasopressins

Topics: Animals; Anti-Bacterial Agents; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Benzeneacetamides; Body Water; Demeclocycline; Diabetes Insipidus; Dogs; Humans; Kidney; Liver Cirrhosis; Liver Cirrhosis, Experimental; Loop of Henle; Pyrrolidines; Rats; Receptors, Opioid; Vasopressins; Water-Electrolyte Balance

Topics: Acute Disease; Catheterization; Endoscopy, Gastrointestinal; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Liver Transplantation; Portasystemic Shunt, Surgical; Radiography; Rupture, Spontaneous; Sclerotherapy; Somatostatin; Vasopressins

Topics: Adrenergic beta-Antagonists; Ascites; Carcinoma, Hepatocellular; Catheterization; Diuretics; Hemorrhage; Hepatic Encephalopathy; Humans; Hypertension, Portal; Liver Cirrhosis; Liver Neoplasms; Nitroglycerin; Peritonitis; Somatostatin; Vasopressins

Topics: Animals; Ascites; Body Water; Humans; Kidney; Liver Cirrhosis; Prostaglandins; Vasopressins

A continuous IV infusion of vasopressin was administrated to a patient with cirrhosis of the liver and acute gastrointestinal bleeding from esophageal varices. In the first 24 hours, the patient developed rhabdomyolysis and cutaneous necrosis. Stopping vasopressin infusion resulted in relief of these lesions. The rarity of these complications suggests an idiosyncratic reaction of susceptible individuals that may be related to previous vascular disease or a failure in baroreceptor regulation.

Topics: Aged; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Infusions, Intravenous; Liver Cirrhosis; Male; Necrosis; Rhabdomyolysis; Skin Diseases; Vasopressins

Topics: Ascites; Atrial Natriuretic Factor; Hemodynamics; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Renin-Angiotensin System; Vasodilator Agents; Vasopressins

Topics: Blood Volume; Combined Modality Therapy; Heart Failure; Humans; Hyponatremia; Inappropriate ADH Syndrome; Liver Cirrhosis; Nephrotic Syndrome; Vasopressins

Topics: Gastrointestinal Hemorrhage; Hemostatic Techniques; Humans; Liver Cirrhosis; Sclerosing Solutions; Surgical Sponges; Vasopressins

Portal hypertension may be caused by portal venous outflow obstruction, an increased portal venous inflow due to a hyperdynamic circulation or both. Portal venous collaterals usually develop above a threshold portal venous pressure of 10 to 12 mm Hg. Only about one third of patients with esophageal varices eventually bleed. However, the mortality in patients who do bleed is high (around 50%) mostly because patients frequently die prior to hospital admission. Immediate endoscopy for precise location of site of bleeding is essential. Bleeding then may be controlled by drugs which lower portal pressure, balloon-tube tamponade or emergency injection sclerotherapy. Of these therapeutic options sclerotherapy probably has the highest success rate for the acute control of variceal bleeding. It can in addition be combined with the initial endoscopic diagnostic procedure, and repeated injection sclerotherapy can reduce the incidence of recurrent variceal bleeding. Portasystemic shunts, transection and devascularisation operations are nowadays only used in patients in whom repeated sclerotherapy had failed. Beta-blocking agents may be an alternative for long-term management after variceal bleeding, although the results are controversial. The data regarding prophylaxis of first variceal hemorrhage are conflicting. Prophylactic regimens should only be carried out in the form of controlled trials.

Topics: Balloon Occlusion; Catheterization; Combined Modality Therapy; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Liver Cirrhosis; Propranolol; Sclerotherapy; Vasopressins

Hyponatremia complicates ascitic hepatic cirrhosis with frequency and gravity related to the gravity of the cirrhosis itself. When hyponatremia develops, it worsens the already present secondary hyperaldosteronism and makes therapy with spironolactone inefficacious. From a pathophysiologic viewpoint a pathogenetic role in determining hyponatremia is attributable to the reduced plasmatic renal perfusion; in several patients a syndrome of inappropriate ADH secretion develops. Other neurohormonal systems (catecholamines, prostaglandins, natriuretic hormones) are probably very important in modifying renal hemodynamics and renal tubular function. In some patients a causative role for hyponatremia is attributable to iatrogenic factors (e.g.: diuretics). From a therapeutic viewpoint, we examine some schedules, pharmacologic or not, that, however, are far from being useful for all patients. We discuss, mainly, water restriction, osmotic diuretics with or without loop diuretics, loop diuretics followed by sodium reintegration and concentration-reinfusion of ascites or application of peritoneovenous shunt.

Topics: Ascites; Humans; Hyponatremia; Liver Cirrhosis; Vasopressins

Drugs used to treat portal hypertension cause constriction of mesenteric arterioles, reducing inflow to the portal venous system, portal pressure, and flow through portasystemic collaterals (such as esophageal varices). Vasopressin and somatostatin are direct vasoconstrictors. Propranolol acts by blocking vasodilatory beta 1 receptors and reducing cardiac output. A major side effect of vasopressin therapy is impaired cardiac performance secondary to coronary vasoconstriction and increased work against high arterial pressure. Infusion of vasopressin together with a cardiac inotrope or a vasodilator, and administration of vasopressin as an inactive "hormonogen" which is slowly released in vivo, may lessen adverse effects. Somatostatin appears to act selectively in the mesenteric circulation. Controlled trials indicate that vasopressin may be useful for controlling hemorrhage from esophageal varices and that somatostatin works at least as well as vasopressin. Propranolol treatment has been used to prevent variceal bleeding; however, controlled trials of its effectiveness have produced conflicting results.

Topics: Animals; Clinical Trials as Topic; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemodynamics; Humans; Hypertension, Portal; Liver Cirrhosis; Portal System; Propranolol; Somatostatin; Vasopressins

The ability of the kidneys to excrete sodium and free water is often impaired in patients with cirrhosis. Sodium retention is a sine qua non for ascites formation. The impairment of water excretion causes hyponatremia and hypo-osmolality. In addition, these patients frequently have functional renal failure caused by intense renal vasoconstriction. The renin-angiotensin-aldosterone system and the sympathetic nervous system, which are activated in most cirrhotic patients with ascites, and a nonosmotic hypersecretion of antidiuretic hormone are important mechanisms of sodium and water retention. Angiotensin II and sympathetic nervous activity may also be involved in the pathogenesis of functional renal failure. The renal production of prostaglandins is increased in cirrhotic patients with ascites as a homeostatic response to antagonize the vascular effect of endogenous vasoconstrictors and the tubular action of antidiuretic hormone. Nonsteroidal anti-inflammatory drugs should, therefore, be administered with caution in these patients because they may induce acute renal failure and water retention. Although sulindac inhibits the renal synthesis of prostaglandins in cirrhotic patients with ascites, it appears to have less effect on renal function than do other nonsteroidal anti-inflammatory drugs administered to these patients.

Topics: Anti-Inflammatory Agents; Ascites; Atrial Natriuretic Factor; Body Water; Diuretics; Hemodynamics; Humans; Kidney; Liver Cirrhosis; Prostaglandins; Renin-Angiotensin System; Sodium; Sulindac; Sympathetic Nervous System; Vasopressins

Topics: Hemodynamics; Humans; Kinetics; Liver Circulation; Liver Cirrhosis; Nitrates; Propranolol; Vasopressins

It is apparent that renal water retention in patients with advanced liver disease constitutes a fascinating clinical constellation with numerous and diverse causes and an elusive pathophysiology. The dissociation between elevated AVP levels and the attendant changes in renal water handling under diverse experimental conditions, and the demonstration of an impairment in renal water excretion in response to prostaglandin synthetase inhibition, underscore the multifactorial nature of the derangement. It is likely that the development of impaired renal water handling is attributable to a panoply of several hormonal or neural mediators, or both, acting in concert. Additional insight into this fascinating problem must await further characterization of some of the mediators and a delineation of their pathophysiologic role.

Topics: Body Water; Catecholamines; Glomerular Filtration Rate; Humans; Hyponatremia; Kidney; Liver Cirrhosis; Liver Diseases; Prostaglandins; Sympathetic Nervous System; Vasopressins; Water-Electrolyte Imbalance

Topics: Age Factors; Animals; Ascites; Blood; Body Water; Heart Diseases; Humans; Kidney Failure, Chronic; Liver Cirrhosis; Osmolar Concentration; Rats; Renal Dialysis; Ultrafiltration; Vasopressins

Topics: Blood Flow Velocity; Embolization, Therapeutic; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Portasystemic Shunt, Surgical; Propranolol; Receptors, Adrenergic, alpha; Sclerosing Solutions; Somatostatin; Vasopressins

Topics: Acute Disease; Embolization, Therapeutic; Esophageal and Gastric Varices; Esophagus; Gastrointestinal Hemorrhage; Hemostatic Techniques; Humans; Hypertension, Portal; Intubation; Intubation, Gastrointestinal; Liver Cirrhosis; Sclerosing Solutions; Vasopressins

Edema is a collection of fluid within the body's interstitial space which occurs when there is an alteration of the Starling forces which control transfer of fluid from the vascular compartment to surrounding tissue spaces. Generalized edema results when altered Starling forces affect all capillary beds, such as occurs in cardiac failure, cirrhosis, and nephrotic syndrome. Common to these conditions is the development of increased total body sodium and water content. The kidneys play an essential role in the retention of this sodium and water. In this article we shall discuss the signals the kidneys receive for sodium and water retention in these edematous disorders (afferent mechanisms). We shall also examine the means by which the kidney responds to these signals and retains sodium and water (efferent mechanisms). As shall become apparent these edematous states may share many of the same afferent and efferent mechanisms for sodium and water retention.

Topics: Blood Volume; Body Water; Cardiac Output; Edema; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Liver Cirrhosis; Nephrotic Syndrome; Renal Circulation; Renin-Angiotensin System; Sodium; Vasopressins

Vasopressin is capable of being stimulated by several nonosmotic factors such as hypovolemia, hypotension, pharmacologic agents and stress. Vasopressin levels of only 1-2 pg/ml are capable of decreasing substantially renal water excretion. If water is ingested or given intravenously in this setting, positive water balance with hypotonicity and hyponatremia of extracellular fluid (ECF) occur. Such dilution of the ECF results in water movement into cells and potential central nervous system complications [3]. Many disorders (see Tab. 1) may be associated with nonosmotic stimulation of vasopressin release. In these clinical settings, judicious administration of free water and monitoring of serum sodium concentration is necessary. A knowledge of clinical conditions associated with vasopressin-mediated water retention may have therapeutic implications as well. Thus, in recent years it has become appreciated that selected pharmacologic agents such as lithium and demeclocycline can impair the water retaining property of vasopressin [26]. Although lithium appears too toxic for routine usage, demeclocycline has proved to be efficacious therapy in some patients with high vasopressin levels and hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone who are unable to limit their water intake [9]. More recently, other compounds that selectively antagonize the hydro-osmotic effect of vasopressin are being tested and soon may be available [13].

Topics: Adrenal Cortex Diseases; Blood Volume; Diuresis; Extracellular Space; Humans; Hyponatremia; Hypothyroidism; Inappropriate ADH Syndrome; Liver Cirrhosis; Osmosis; Respiratory Insufficiency; Vasopressins

Topics: Acid-Base Equilibrium; Aldosterone; Angiotensin II; Animals; Blood Volume; Catecholamines; Diuresis; Dogs; Humans; Immersion; Kidney; Kidney Diseases; Liver Cirrhosis; Natriuresis; Parathyroid Hormone; Phosphates; Potassium; Primates; Prostaglandins; Renin; Temperature; Vasopressins; Water-Electrolyte Balance

Topics: Acidosis, Renal Tubular; Aldosterone; Ascites; Diuretics; Hepatic Encephalopathy; Humans; Hypokalemia; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubules, Distal; Liver Cirrhosis; Liver Transplantation; Sodium; Transplantation, Homologous; Uremia; Vasopressins; Water-Electrolyte Imbalance

Topics: Catheterization; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hepatic Veins; Humans; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Portacaval Shunt, Surgical; Portal Vein; Prospective Studies; Radiography; Regional Blood Flow; Vasopressins; Venous Pressure

Topics: Anti-Bacterial Agents; Blood Transfusion; Cryotherapy; Drainage; Esophageal and Gastric Varices; Esophageal Perforation; Gastrointestinal Hemorrhage; Hemostasis; Hepatic Encephalopathy; Humans; Hypertension, Portal; Intubation, Gastrointestinal; Liver Cirrhosis; Myocardial Infarction; Peptic Ulcer; Pneumonia, Aspiration; Portacaval Shunt, Surgical; Sclerosing Solutions; Therapeutic Irrigation; Ulcer; Vasopressins; Vitamin K

Topics: Acetylcholine; Acute Kidney Injury; Angiotensin II; Animals; Bradykinin; Diuretics; Dogs; Dopamine; Electric Stimulation; Epinephrine; Heart Failure; Hemorrhage; Humans; Hypotension; Isoproterenol; Kidney Cortex; Kidney Transplantation; Liver Cirrhosis; Norepinephrine; Oxytocin; Prostaglandins; Regional Blood Flow; Transplantation, Homologous; Ureter; Vasomotor System; Vasopressins; Vena Cava, Inferior; Water-Electrolyte Balance

Topics: Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemodynamics; Humans; Liver Cirrhosis; Vasopressins

Topics: Diverticulum, Esophageal; Hemorrhage; Humans; Hypertension, Portal; Ligation; Liver Cirrhosis; Portacaval Shunt, Surgical; Tampons, Surgical; Vasopressins

Topics: Addison Disease; Ascites; Edema; Extracellular Space; Heart Failure; Humans; Hyponatremia; Intestinal Secretions; Kidney Failure, Chronic; Liver Cirrhosis; Potassium; Sodium; Vasopressins; Water-Electrolyte Balance

Topics: Animals; Body Fluids; Cell Membrane Permeability; Chlorides; Dogs; Extracellular Space; Heart Failure; Humans; Hyponatremia; Infant Nutrition Disorders; Kidney; Liver Cirrhosis; Neoplasms; Osmolar Concentration; Potassium; Respiratory Insufficiency; Sodium; Vasopressins; Water; Whipple Disease

Topics: Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Hyperaldosteronism; Liver Cirrhosis; Potassium; Rest; Sodium; Vasopressins; Vitamins

Topics: Acute Kidney Injury; Animals; Blood; Cardiac Glycosides; Dehydration; Diuretics; Glomerular Filtration Rate; Heart Failure; Hyponatremia; Kidney Failure, Chronic; Liver Cirrhosis; Mineralocorticoid Receptor Antagonists; Nephrotic Syndrome; Sodium; Syndrome; Vasopressins; Water

Topics: Age Factors; Blood Transfusion; Emergencies; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Middle Aged; Peptic Ulcer Hemorrhage; Tampons, Surgical; Vagotomy; Vasopressins

Topics: Aldosterone; Angiotensin II; Ascites; Humans; Juxtaglomerular Apparatus; Kidney; Liver; Liver Cirrhosis; Renin; Sodium; Vasopressins

Topics: Budd-Chiari Syndrome; Chemical and Drug Induced Liver Injury; Collateral Circulation; Epinephrine; Hepatic Artery; Humans; Hypertension, Portal; Hypoxia; Liver Circulation; Liver Cirrhosis; Liver Diseases; Norepinephrine; Portal System; Vasopressins; Venous Pressure

Topics: Adrenal Glands; Aldosterone; Diagnosis, Differential; Edema; Extracellular Space; Female; Heart Diseases; Humans; Kidney; Kidney Diseases; Liver Cirrhosis; Male; Parasitic Diseases; Pituitary Gland; Posture; Pre-Eclampsia; Pregnancy; Pulmonary Edema; Sodium; Vasopressins; Water-Electrolyte Balance

Topics: Adrenal Insufficiency; Animals; Congenital Hypothyroidism; Diabetes Insipidus; Heart Failure; Humans; Liver Cirrhosis; Osmolar Concentration; Pituitary Diseases; Vasopressins

Topics: Adrenal Cortex Hormones; Aldosterone; Ascites; Diet Therapy; Edema; Humans; Liver Cirrhosis; Lymphatic System; Proteins; Vasopressins; Water-Electrolyte Balance

Terlipressin is a vasopressin analogue used for its potent V1a effects in cirrhotic patients. Recent data suggest that terlipressin has affinity to renal V2 receptors and modulates Aquaporin 2 (AQP2) expression and free water clearance. Stimulation of renal V2 receptors may also affect sodium transport via the Epithelial Sodium Channel (ENaC). Furthermore, endothelial V2 receptors may indirectly affect proximal sodium handling by increasing plasma cAMP.. We investigated 18 patients with cirrhosis and ascites before and after infusion of 2 mg of terlipressin. Plasma cAMP and urine AQP2 were measured and a newly developed radioimmunoassay was used to quantify ENaC in the urine.. Mean arterial blood pressure increased from 87 ± 15 to 105 ± 19 mmHg, p < 0.001 after terlipressin infusion and GFR increased from 52 ± 6 to 69 ± 9 mL/min, p < 0.01. Urine-ENaC in ng/mmol creatinine increased from 42 ± 6 to 50 ± 7 ng/mmol creatinine, p = 0.05. Urine sodium increased from 43 ± 8 to 62 ± 9 mmol/L, p < 0.01. Plasma cAMP was not affected by terlipressin, 106 (63-673) vs. 103.5 (69-774) pmol/mL, NS. The rise in ENaC excretion correlated with the rise in AQP2 excretion, r = 0.63, p < 0.01. There was a weak correlation between the change in MAP and the rise in AQP2 excretion (p < 0.05).. Increased ENaC excretion suggests increased abundance of ENaC and resultant increased distal sodium reabsorption. The V2 effects of terlipressin are insufficient to stimulate the endothelial V2 receptors since plasma cAMP is unaltered. Despite pronounced V1a and some V2 effects of terlipressin, additional effects on proximal sodium handling are therefore not likely.

Topics: Antihypertensive Agents; Cyclic AMP; Demography; Epithelial Sodium Channels; Female; Humans; Kidney; Liver Cirrhosis; Lypressin; Male; Middle Aged; Receptors, Vasopressin; Sodium; Terlipressin; Vasopressins; Water-Electrolyte Balance

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.. 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).. 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).. This study showed no differences in the effectiveness of somatostatin and vasopressin, but the somatostatin group had a lower risk of the complications.

Topics: Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Hemostatics; Humans; Infusions, Intravenous; Liver Cirrhosis; Male; Middle Aged; Prospective Studies; Somatostatin; Treatment Outcome; Vasopressins

Water retention and dilutional hyponatremia, mainly attributable to an impairment of free water excretion and increased vasopressin activity, are well-documented complications in cirrhotic patients with ascites. VPA-985 is a selective, nonpeptide, orally active, vasopressin-2-receptor antagonist. The aim of this study was to determine the pharmacodynamics, safety, and pharmacokinetics of ascending single doses (25, 50, 100, 200, and 300 mg) in cirrhotic patients with ascites in a randomized, double-blind, placebo-controlled trial. Each dose level was studied in 5 patients (4 active and 1 placebo). After an overnight fast and fluid restriction (continued for 4 hours after dose administration), all patients were given placebo on baseline day and an oral suspension of VPA or placebo on the following day. VPA produced a significant dose-related increase in daily urine output (1,454 +/- 858 mL to 4,568 +/- 4,385 mL with VPA 300 mg) and a dose-related decrease in urine osmolality. The free water clearance reached greater than 3 mL/min for doses 100 mg or greater. Simultaneously, significant increases in serum osmolality, sodium, and vasopressin levels were found. There was a significant increase in sodium urine excretion. VPA was rapidly absorbed and maximum serum concentrations were achieved within 1 hour after administration. Elimination half-life ranged from 9.0 hours after 100 mg to 22.6 hours after 200 mg. In conclusion, VPA induced a dose-related aquaretic response, suggesting a therapeutic potential in managing water retention in patients with liver cirrhosis with ascites.

Topics: Adult; Aged; Antidiuretic Hormone Receptor Antagonists; Ascites; Azepines; Benzamides; Double-Blind Method; Drinking; Electrolytes; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Osmolar Concentration; Pyrroles; Renin; Sodium; Urine; Urodynamics; Vasopressins; Water; Water-Electrolyte Balance

Topics: Catheterization; Emergencies; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostatics; Humans; Liver Cirrhosis; Portacaval Shunt, Surgical; Survival Rate; Vasopressins

The mechanism(s) of hyponatremia of cirrhosis is not completely clarified. Although increased vasopressin activity has been proposed in some studies, there have been reports disputing its role in the pathogenesis of profound hyponatremia in patients with decompensated liver disease. Methodologic flaws and lack of correlation with indices of circulatory dysfunction may have contributed to these discrepancies. The aims of the present study were to measure levels of vasopressin both in plasma and in urine and to correlate them with the volume-dependent hormonal systems of plasma renin activity (PRA) and atrial natriuretic factor (ANF).. Plasma vasopressin, ANF, and PRA were measured by radioimmunoassay in 19 patients with cirrhosis, ascites, and severe hyponatremia (mean serum sodium, 121.8 mmol/l) and 11 patients with cirrhosis and normal serum sodium (mean, 137.6 mmol/l). Vasopressin levels were also assessed by radioimmunoassay in urine.. Patients with hyponatremia had higher plasma and urine vasopressin levels than patients with normal serum sodium concentrations (plasma, 2.9 versus 1.0 pg/ml, P = 0.0009; urine, 38.3 versus 12.3 ng/g creatinine, P = 0.0008). PRA was higher (4.8 versus 1.0 ng/ml/h, P = 0.0004) and plasma ANF lower (111.1 versus 148.7 pg/ml, P = 0.01) in patients with hyponatremia.. These results indicate that plasma and urine vasopressin levels are inappropriately increased in patients with cirrhosis and severe hyponatremia. The concomitant increase of PRA and decrease of plasma ANF suggest that decreased 'effective' plasma volume generates nonosmotic stimuli for vasopressin hypersecretion in these patients.

Topics: Adult; Aged; Atrial Natriuretic Factor; Diuretics; Female; Humans; Hyponatremia; Kidney Function Tests; Liver Cirrhosis; Male; Middle Aged; Plasma Volume; Prognosis; Radioimmunoassay; Reference Values; Renin; Survival Rate; Urinalysis; Vasopressins

The effects of vasopressin plus oxygen and vasopressin alone on gastric mucosal perfusion and oxygenation were studied using reflectance spectrophotometry and laser Doppler velocimetry in 23 cirrhotic patients with portal-hypertensive gastropathy. The measurements were performed under basal conditions and after double-blinded administration of placebo (n = 7), vasopressin (0.3 U/min; n = 8) or vasopressin (0.3 U/min) plus nasal oxygen (4 L/min; n = 8). No significant effects on gastric mucosal haemodynamics and oxygenation were observed after placebo. In contrast, vasopressin and vasopressin plus oxygen induced a similar reduction in haemoglobin content (-26 +/- 2 and -21 +/- 4%, respectively P < 0.01), and laser Doppler signal (-23 +/- 2 and -22 +/- 2%, respectively, P < 0.01). Although each treatment induced a significant reduction in oxygen saturation (-21 +/- 2 and -7 +/- 1%, respectively P < 0.01), the effect was less pronounced in patients receiving the combination than in those receiving vasopressin alone (P < 0.01). These data suggest that vasopressin and vasopressin plus oxygen reduce gastric mucosal hyperaemia and that the oxygen supplement partially protects against gastric mucosal hypoxia during vasopressin infusion in cirrhotic patients with portal-hypertensive gastropathy.

Topics: Aged; Analysis of Variance; Combined Modality Therapy; Double-Blind Method; Female; Gastric Mucosa; Hemodynamics; Humans; Hypertension, Portal; Laser-Doppler Flowmetry; Liver Cirrhosis; Male; Middle Aged; Oxygen; Oxygen Inhalation Therapy; Spectrophotometry; Stomach Diseases; Vasopressins

To compare hepatic artery hemodynamic response to altered portal blood flow in normal and cirrhotic livers.. The portal blood flow and hepatic artery pulsatility index were measured by means of duplex ultrasound before and after subjects (eight control subjects and 10 cirrhotic patients) ingested a 500-kcal mixed-liquid meal and during intravenous infusion of vasopressin at a rate of 0.3 U/min (nine control and nine cirrhotic subjects). The hepatic artery buffer index (ratio of maximum change from baseline in hepatic artery pulsatility index to maximum change from baseline in portal blood flow) was also calculated.. Meal consumption increased the portal blood flow and hepatic artery pulsatility index in all subjects. The hepatic artery buffer index, however, was significantly lower in cirrhotic than in control subjects (0.67 min/L +/- 0.06 [standard error of the mean] vs 1.54 min/L +/- 0.20, respectively; P < .01). Vasopressin infusion decreased the portal blood flow and hepatic artery pulsatility index in all subjects. Again, the hepatic artery buffer index was significantly lower in cirrhotic than in control subjects (0.28 min/L +/- 0.07 vs 0.50 min/L +/- 0.04, respectively; P < .05).. Hepatic artery vascular responsiveness to altered portal blood flow is blunted in cirrhotic livers.

Topics: Fasting; Female; Hemodynamics; Hepatic Artery; Humans; Liver Circulation; Liver Cirrhosis; Male; Middle Aged; Observer Variation; Prospective Studies; Reference Values; Time Factors; Ultrasonography, Doppler, Duplex; Vasoconstrictor Agents; Vasopressins

Vasopressin reduces portal pressure which may be due to decreased portal inflow. However, it remains unclear whether vasopressin is able to selectively reduce esophageal varices blood flow. The aim of this study was to address this question.. Fifteen patients with cirrhosis and esophageal varices were included in this prospective study. Portal vein and superior mesenteric artery flow velocity were measured with a percutaneous echo-Doppler. Esophageal varices flow velocity was measured using a transesophageal echo-Doppler technique. Mean arterial pressure and heart rate were also recorded. These measurements were performed at baseline condition and 15 min after observer blind drug administration. In this study, two groups, six patients receiving placebo and nine patients receiving 0.3 U/min of vasopressin, were randomized according to the coded number.. Placebo administration had no effect on systemic and splanchnic circulation. In contrast, vasopressin administration increased mean arterial pressure (p < 0.05) associated with a bradycardia (p < 0.01). In splanchnic circulation, vasopressin decreased portal vein (-32 +/- 3%, p < 0.01), superior mesenteric artery (-30 +/- 2%, p < 0.01), and esophageal varices flow velocity (-48 +/- 5%, p < 0.01). When the magnitude of these reductions was compared, ANOVA showed a significant difference (p < 0.01). Furthermore, the reduction in esophageal varices flow velocity was significantly higher than that in portal vein flow velocity (p < 0.01) and that in superior mesenteric artery flow velocity (p < 0.01).. These data support the view that vasopressin is able to selectively reduce esophageal varices blood flow. This effect, in addition to its well-established portal pressure reducing action, may play a role in its therapeutic efficacy in the treatment of variceal bleeding.

Topics: Aged; Blood Flow Velocity; Blood Pressure; Esophageal and Gastric Varices; Female; Heart Rate; Humans; Infusions, Intravenous; Liver Cirrhosis; Male; Mesenteric Artery, Superior; Middle Aged; Portal Vein; Prospective Studies; Ultrasonography, Doppler; Vasoconstrictor Agents; Vasopressins

Topics: Acute Disease; Double-Blind Method; Gastric Mucosa; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Liver Cirrhosis; Lypressin; Perfusion; Stomach Diseases; Terlipressin; Vasoconstrictor Agents; Vasopressins

Time-velocity wave-form analysis of Doppler signals from small intrarenal arteries allows estimation of intrarenal arteriolar vascular resistance. Among the various indexes proposed, the resistive index is the most widely used for this estimation. To investigate whether the resistive index is useful in the diagnosis of functional kidney failure and prediction of survival in cirrhotic patients with ascites, we measured resistive index, kidney and liver function and plasma levels of renin, aldosterone and antidiuretic hormone in 10 healthy subjects, 12 patients with compensated cirrhosis and 32 patients with cirrhosis and ascites (17 with kidney failure). A total of 28 clinical and laboratory variables were analyzed for prognostic value. Resistive index was significantly increased in patients with kidney failure (0.74 +/- 0.01) compared with those in the other three groups (0.64 +/- 0.01, 0.64 +/- 0.02 and 0.67 +/- 0.01) and correlated significantly with glomerular filtration rate, arterial pressure, plasma renin activity and free water clearance in the cirrhotic patients. The sensitivity and specificity of the resistive index in detecting kidney failure in patients with ascites were 71% and 80%, respectively. Nine variables were correlated with survival in the univariate analysis, including resistive index, age, hepatomegaly, blood urea nitrogen, serum creatinine, plasma sodium concentration, glomerular filtration rate, plasma renin activity and plasma concentration of antidiuretic hormone. Multivariate analysis disclosed only three independent predictors of survival: plasma renin activity, plasma concentration of antidiuretic hormone and serum sodium concentration. In conclusion, resistive index is a sensitive method to assess intrarenal hemodynamics in patients with cirrhosis and ascites. It also has predictive value for survival in these patients.

Topics: Analysis of Variance; Blood Pressure; Female; Glomerular Filtration Rate; Humans; Liver Cirrhosis; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prognosis; Regression Analysis; Renal Artery; Renal Insufficiency; Renin; Sensitivity and Specificity; Sodium; Survival Rate; Ultrasonography, Doppler; Vascular Resistance; Vasopressins

A prospective randomized trial was conducted in unselected, consecutive patients with bleeding esophageal varices resulting from cirrhosis comparing (1) emergency portacaval shunt performed within 8 hr of initial contact (21 patients) with (2) emergency medical therapy (intravenous vasopressin and esophageal balloon tamponade) followed in 9 to 30 days by elective portacaval shunt in survivors (22 patients). All patients underwent the same diagnostic workup within 3 to 6 hr of initial contact, and received identical supportive therapy initially. All patients were followed up for at least 10 yr. The protocol contained no escape or cross-over provisions. There were no statistically significant differences between the two treatment groups in the incidence of any of the clinical variables, results of laboratory tests or degree of portal hypertension. Child's risk classes in the shunt group were A-2 patients, B-8 patients and C-11 patients, whereas in the medical group they were A-10 patients, B-5 patients, and C-7 patients, a significant difference (p < 0.01) that might have favored emergency medical treatment. Bleeding was controlled initially and permanently by emergency shunt in every patient, but by medical therapy in only 45% (p < 0.001). Mean requirement for blood transfusion was 7.1 +/- 2.6 units in the shunt group and 21.4 +/- 2.6 units in the medical group (p < 0.001). Eighty-one percent of the patients in the shunt group were discharged alive compared with 45% in the medical group (p = 0.027). Five- and 10-yr observed survival rates were 67% and 57%, respectively, after emergency shunt compared with 18% and 18%, respectively, after the combination of emergency medical therapy and elective shunt (p < 0.01). These survival rates produced by emergency shunt performed within 8 hr of initial contact confirm the effectiveness of this procedure observed in our previous unrandomized studies.

Topics: Adult; Aged; Balloon Occlusion; Catheterization; Emergencies; Esophageal and Gastric Varices; Esophagus; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Portacaval Shunt, Surgical; Prospective Studies; Quality of Life; Survival Rate; Vasopressins

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.

Topics: Administration, Cutaneous; Adult; Aged; Drug Therapy, Combination; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Lypressin; Male; Middle Aged; Nitroglycerin; Terlipressin; Vasopressins

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

Topics: Double-Blind Method; Female; Gastric Mucosa; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Hyperemia; Hypertension, Portal; Laser-Doppler Flowmetry; Liver Cirrhosis; Lypressin; Male; Middle Aged; Oxygen; Regional Blood Flow; Spectrophotometry; Stomach Diseases; Terlipressin; Vasopressins

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.

Topics: Aged; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypertension, Portal; Liver; Liver Cirrhosis; Male; Middle Aged; Nicardipine; Splanchnic Circulation; Vasopressins

This randomized controlled trial was conducted to compare the efficacy of intravenous infusion of octreotide (a synthetic long-acting somatostatin analogue) with vasopressin in 48 cirrhotic patients with endoscopically proven bleeding esophageal varices. Twenty-four patients received a continuous infusion of octreotide 25 micrograms/h for 24 h after an initial bolus of 100 micrograms and another 24 patients received a continuous infusion of vasopressin 0.4 U/min for 24 h. Bleeding was initially controlled after 6 h of drug infusion in 88% (21/24) and 54% (13/24) of the patients treated with octreotide and vasopressin respectively (p = 0.03). Complete control of bleeding after 24 h of drug infusion was achieved in 15 (63%) patients receiving octreotide and in 11 (46%) patients receiving vasopressin (p > 0.05). Side effects during drug infusion such as headache, chest pain and abdominal pain were significantly lower in the octreotide group (3/24) than in the vasopressin group (11/24). Serum gastrin and insulin levels fell significantly following octreotide infusion, but plasma glucose levels remained unchanged. Mortality related to bleeding esophageal varices was no different between the two groups. This report showed that octreotide infusion was more effective and had fewer side effects than vasopressin in initial controlling of acute esophageal variceal bleeding until an elective endoscopic sclerotherapy could be performed.

Topics: Aged; Blood Glucose; Esophageal and Gastric Varices; Female; Gastrins; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Injections, Intravenous; Insulin; Liver Cirrhosis; Male; Middle Aged; Octreotide; Vasopressins

We measured the hemodynamic effects of intravenous vasopressin, ketanserin (a 5-hydroxytryptamine-2 receptor blocker), and vasopressin plus ketanserin in 33 patients with hepatitis B-related cirrhosis. Thirteen patients received vasopressin alone (0.66 units/min), ten patients ketanserin alone (10 mg), and ten patients vasopressin followed by vasopressin plus ketanserin. Vasopressin alone reduced the hepatic venous pressure gradient (from 18 +/- 5, mean +/- S.D., to 9 +/- 3 mmHg, p less than 0.0001) and cardiac output (p less than 0.0001), but increased mean arterial pressure (p less than 0.005), mean pulmonary arterial pressure (p less than 0.0001), pulmonary capillary wedge pressure (p less than 0.0001), and systemic vascular resistance (p less than 0.001). There was no significant change in heart rate. Ketanserin alone produced a significant fall in the hepatic venous pressure gradient (from 16 +/- 4 to 13 +/- 3 mmHg, p less than 0.0001), mean arterial pressure (p less than 0.005), mean pulmonary arterial pressure (p less than 0.005), and pulmonary capillary wedge pressure (p less than 0.005). Heart rate, cardiac output, and systemic vascular resistance were not significantly changed. The addition of ketanserin to vasopressin corrected most of the systemic hemodynamic disturbances produced by vasopressin. This combination did not lead to a further reduction in the hepatic venous pressure gradient. We conclude that intravenous ketanserin reduces portal pressure in patients with hepatitis B-related cirrhosis. The addition of ketanserin to vasopressin improves the detrimental systemic hemodynamic effects of vasopressin without further reducing the portal pressure.

Topics: Aged; Blood Pressure; Cardiac Output; Drug Therapy, Combination; Female; Heart Rate; Hemodynamics; Hepatitis B; Humans; Infusions, Intravenous; Ketanserin; Liver; Liver Cirrhosis; Male; Middle Aged; Vasopressins

We have evaluated the haemodynamic effects of intravenous (iv) nitroglycerin (NG) and vasopressin (VP) alone and in combination, in 12 patients with cirrhosis and recent variceal haemorrhage (two to seven days). Nitroglycerin infusion alone (200 micrograms/min) produced a significant fall in portal pressure (WHVP-FHVP) (from 16.4 (0.6) to 13.3 (1.2) mmHg; p less than .001) associated with hypotension (mean arterial pressure from 95 (7) to 78 (9) mmHg; p less than 0.005). Vasopressin alone (0.4 IU/min) reduced portal pressure (20.7 (1.3) to 14.0 (1.3) mmHg; p less than 0.001), but there was considerable variation in the systemic haemodynamic changes with increased cardiac output in four of six patients. The combination of vasopressin and nitroglycerin corrected all systemic haemodynamic disturbances produced by either agent alone. This combination led, however, to a further reduction in portal pressure (from 13.7 (0.9) to 11.7 (0.7) mmHg p less than 0.01). These results show that: (1) intravenous nitroglycerin reduces portal pressure, and (2) the combination of nitroglycerin and vasopressin reverses systemic haemodynamic disturbances produced by either agent alone and leads to a further decrease in portal pressure.

Topics: Drug Therapy, Combination; Female; Gastrointestinal Hemorrhage; Hemodynamics; Humans; Hypertension, Portal; Injections, Intravenous; Liver Circulation; Liver Cirrhosis; Male; Nitroglycerin; Vasopressins

Drugs used to treat portal hypertension cause constriction of mesenteric arterioles, reducing inflow to the portal venous system, portal pressure, and flow through portasystemic collaterals (such as esophageal varices). Vasopressin and somatostatin are direct vasoconstrictors. Propranolol acts by blocking vasodilatory beta 1 receptors and reducing cardiac output. A major side effect of vasopressin therapy is impaired cardiac performance secondary to coronary vasoconstriction and increased work against high arterial pressure. Infusion of vasopressin together with a cardiac inotrope or a vasodilator, and administration of vasopressin as an inactive "hormonogen" which is slowly released in vivo, may lessen adverse effects. Somatostatin appears to act selectively in the mesenteric circulation. Controlled trials indicate that vasopressin may be useful for controlling hemorrhage from esophageal varices and that somatostatin works at least as well as vasopressin. Propranolol treatment has been used to prevent variceal bleeding; however, controlled trials of its effectiveness have produced conflicting results.

Topics: Animals; Clinical Trials as Topic; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemodynamics; Humans; Hypertension, Portal; Liver Cirrhosis; Portal System; Propranolol; Somatostatin; Vasopressins

The activity of demeclotetracyclin, and ADH antagonist, is studied in 11 ethylic patients with cirrhosis of the liver, under a large hydric diet (1500 cm3). The prescription of the cyclin (600 mg daily) is always determined by a fall of the urinary osmolarity (-36%) and by a dramatic improvement of the free water clearance (+ 60%); consecutively, we observe an increase of natremia in 8 out of 9 cases. Associated with Spironolactone (200 mg daily) the anti-ADH activity persists (the free water clearance becomes positive in 5 out of 10 patients), in spite of the natriuretic activity of anti-aldosterone ; a minimal fall of the natremia is observed in only 2 cases. The indication of Demeclotetracyclin in the curative or preventive treatment of the hyponatremia of the liver cirrhosis is discussed.

Topics: Adult; Aged; Ascites; Clinical Trials as Topic; Demeclocycline; Drug Therapy, Combination; Edema; Female; Humans; Hyponatremia; Liver Cirrhosis; Male; Middle Aged; Natriuresis; Spironolactone; Vasopressins

Dilutional hyponatremia due to increased plasma arginine vasopressin (AVP) is associated with liver cirrhosis. However, plasma AVP remains elevated despite progressive hypoosmolality. This study investigated changes to inhibitory control of supraoptic nucleus (SON) AVP neurons during liver cirrhosis. Experiments were conducted with adult male Sprague-Dawley rats. Bile duct ligation was used as a model of chronic liver cirrhosis. An adeno-associated virus containing a construct with an AVP promoter and either green fluorescent protein (GFP) or a ratiometric chloride indicator, ClopHensorN, was bilaterally injected into the SON of rats. After 2 weeks, rats received either BDL or sham surgery, and liver cirrhosis was allowed to develop for 4 weeks. In vitro, loose patch recordings of action potentials were obtained from GFP-labeled and unlabeled SON neurons in response to a brief focal application of the GABA

Topics: Animals; Arginine Vasopressin; Bile Ducts; Chlorides; gamma-Aminobutyric Acid; Green Fluorescent Proteins; Hyponatremia; Liver Cirrhosis; Male; Muscimol; Neurons; Rats; Rats, Sprague-Dawley; Supraoptic Nucleus; Vasopressins

The vasopressin system has emerged as a therapeutic focus for lowering portal hypertension and reducing splanchnic vasodilation in patients with refractory ascites. Clinically available vasopressin agonists are limited by preferential selectivity for V1 receptors that also have steep concentration-response curves with potential risks of excess vasoconstriction and/or complete antidiuretic effects. OCE-205 is a novel, selective, partial V1a receptor agonist with mixed agonist/antagonist activity and no V2 receptor activation at therapeutic doses. We carried out two studies assessing the in vivo effects of OCE-205 in different rat models of cirrhosis and ascites. In a carbon tetrachloride rat cirrhosis model, OCE-205 administration produced a marked reduction in portal hypertension and hyperaldosteronism, along with robust diuretic and natriuretic effects. These effects were accompanied by marked decreases in ascites volume, with three of five animals experiencing total mobilization of ascites. There was no evidence of fluid overload or sodium or water retention, confirming OCE-205's lack of V2 receptor activity. In a second, corroborative study using a bile duct ligation rat model of ascites, OCE-205 produced significant decreases in ascites volume and body weight and a significant increase in urine volume versus vehicle. Urine sodium excretion increased significantly after the first administration of OCE-205 relative to vehicle; however, repeat administration over 5 days did not lead to hyponatremia. Thus, in separate in vivo models, the mixed agonist/antagonist OCE-205 demonstrated relevant and expected endpoint findings consistent with its known mechanism of action and in vitro pharmacology without apparent unwanted effects or nonspecific toxicities.

Topics: Animals; Ascites; Diuretics; Hyperaldosteronism; Hypertension, Portal; Liver Cirrhosis; Natriuretic Agents; Rats; Receptors, Vasopressin; Sodium; Vasopressins

Terlipressin is recommended as a gold standard to treat hepatorenal syndrome complicating liver cirrhosis. It is presented as a specific V1A receptor agonist, beyond its enzymatic conversion into lysine. Terlipressin is a non-selective vasopressin analogue, exhibiting intrinsic agonist properties. Its full V2 receptor agonism may result in renal effects potentially aggravating water retention and hyponatremia of cirrhosis.

Topics: Animals; Cell Line; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP; Hepatorenal Syndrome; Humans; Inositol Phosphates; Liver Cirrhosis; Lypressin; Male; Prodrugs; Rats; Rats, Wistar; Receptors, Vasopressin; Terlipressin; Transfection; Vasopressins

During the past 50 years the molecular mechanisms of renal reabsorption of sodium and water have been described and molecules specifically interfering with these mechanisms have been developed (diuretics, vasopressin receptor antagonists). Chronic hyponatremia is caused by relative excess of free water, it occurs within a broad spectrum of diseases associated with hypervolemia (heart failure, liver cirrhosis), normovolemia and hypovolemia and it is a negative prognostic factor for patients with chronic heart failure and cirrhotic ascites. Vaptans (vasopressin antagonists, vasopressin V2-receptor inhibitors) reduce reabsorption of water in the distal nephron, they increase free water excretion and normalize serum concentrations of sodium in normovolemic and hypervolemic conditions associated with hyponatremia. Hyponatremia can be corrected (depending on cause, severity and speed of development) through the reduction of fluid intake, administration of a hypertonic solution NaCl, diuretics, oral administration of urea and by vaptans. The role of vaptans in the treatment of hyponatremia should be defined even better, in Europe vaptans can be used to treat the syndrome of inadequate antidiuretic hormone secretion (SIADH).Key words: hyponatremia - liver cirrhosis - heart failure - syndrome of inadequate secretion ADH - tolvaptan - vasopressin.

Topics: Antidiuretic Hormone Receptor Antagonists; Benzazepines; Europe; Heart Failure; Humans; Hyponatremia; Inappropriate ADH Syndrome; Liver Cirrhosis; Receptors, Vasopressin; Sodium; Tolvaptan; Vasopressins

The role of renal aquaporin-2 (AQP2) water channel turnover in patients with liver cirrhosis, portal hypertension and water retention remains unclear. Transjugular intrahepatic portosystemic shunt (TIPS) insertion reduces portal hypertension, improves water excretion and lowers plasma vasopressin. The aim of this study was to establish whether TIPS insertion decreases urinary AQP2 excretion (uAQP2) in parallel with improved water excretion.. Fourteen cirrhosis patients with refractory ascites were studied before TIPS insertion and 4 and 12 weeks after insertion. A 24-h urine collection was followed by an oral water load (20 ml/kg body weight) with a 4-h blood and urine sampling.. TIPS reduced the portal pressure gradient from a median 18(4) (25-75% InterQuartile-range) to 7(2) mmHg, p < 0.05 and the need for diuretics (p < 0.05). TIPS increased plasma sodium from 136(6) mmol/l to 139(4), (p < 0.05) and diuresis from 1650(1043) ml/24 h to 2230(560) (p < 0.05), although the 24-h urinary sodium excretion did not change. There was no change in the baseline uAQP2 before 274(249) ng/(mmol creatinine/24 h) and 12 weeks after TIPS 242(201). There were no systematic changes in uAQP2, plasma vasopressin or other vasoactive substances during the water loads, before or after TIPS.. The effective amelioration of portal hypertension improved the patient's water excretion and plasma sodium, but there was no change in renal AQP2 trafficking or vasopressin. These findings do not support a primary role for renal AQP2 water channels in portal hypertensive water retention.

Topics: Aquaporin 2; Ascites; Diuresis; Female; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Portal Pressure; Portasystemic Shunt, Transjugular Intrahepatic; Sodium; Vasopressins

Transient receptor potential canonical subtype 4 (TRPC4) is expressed in the magnocellular paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. In this study, the regulation of TRPC4 expression was investigated in water deprivation and hepatic cirrhosis. We used laser capture microdissection technique for precise dissection of pure AVP cell population in the PVN and SON followed by quantitative real-time RT-PCR, and immunodetection techniques by Western blot analysis and immunofluorescence. Bile duct ligation elevated TRPC4 transcripts in the SON but not PVN with correlated changes in the protein expression in these regions, as well as increased colocalization with AVP in the SON, with no changes in the PVN. Water deprivation resulted in increased TRPC4 mRNA expression in the PVN, while it decreased channel expression levels in the SON. In both of these regions, protein expression measured from tissue punches were unaltered following water deprivation, with no changes in the number of TRPC4-positive cells. Thus, TRPC4 expression is differentially regulated in physiological and pathophysiological models of vasopressin release.

Topics: Animals; Arginine Vasopressin; Bile Ducts; Blood Proteins; Blotting, Western; Gene Expression Regulation; Hypothalamus; Ligation; Liver Cirrhosis; Male; Neurons; Osmolar Concentration; Rats; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; TRPC Cation Channels; Vasopressins; Water Deprivation

Hyponatremia is a serious, but often overlooked, electrolyte imbalance that has been independently associated with a wide range of deleterious changes involving many different body systems. Untreated acute hyponatremia can cause substantial morbidity and mortality as a result of osmotically induced cerebral edema, and excessively rapid correction of chronic hyponatremia can cause severe neurologic impairment and death as a result of osmotic demyelination. The diverse etiologies and comorbidities associated with hyponatremia pose substantial challenges in managing this disorder. In 2007, a panel of experts in hyponatremia convened to develop the Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations that defined strategies for clinicians caring for patients with hyponatremia. In the 6 years since the publication of that document, the field has seen several notable developments, including new evidence on morbidities and complications associated with hyponatremia, the importance of treating mild to moderate hyponatremia, and the efficacy and safety of vasopressin receptor antagonist therapy for hyponatremic patients. Therefore, additional guidance was deemed necessary and a panel of hyponatremia experts (which included all of the original panel members) was convened to update the previous recommendations for optimal current management of this disorder. The updated expert panel recommendations in this document represent recommended approaches for multiple etiologies of hyponatremia that are based on both consensus opinions of experts in hyponatremia and the most recent published data in this field.

Topics: Adrenal Insufficiency; Antidiuretic Hormone Receptor Antagonists; Clinical Trials as Topic; Diagnosis, Differential; Diuretics; Gastrointestinal Diseases; Genetic Diseases, X-Linked; Humans; Hyponatremia; Hypothyroidism; Hypovolemia; Inappropriate ADH Syndrome; Liver Cirrhosis; Polydipsia; Receptors, Vasopressin; Sodium Chloride; Vasopressins

Bile duct ligation (BDL), a model of hepatic cirrhosis, is associated with dilutional hyponatremia and inappropriate vasopressin release. ΔFosB staining was significantly increased in vasopressin and oxytocin magnocellular neurosecretory cells in the supraoptic nucleus (SON) of BDL rats. We tested the role of SON ΔFosB in fluid retention following BDL by injecting the SON (n = 10) with 400 nl of an adeno-associated virus (AAV) vector expressing ΔJunD (a dominant negative construct for ΔFosB) plus green fluorescent protein (GFP) (AAV-GFP-ΔJunD). Controls were either noninjected or injected with an AAV vector expressing only GFP. Three weeks after BDL or sham ligation surgery, rats were individually housed in metabolism cages for 1 wk. Average daily water intake was significantly elevated in all BDL rats compared with sham ligated controls. Average daily urine output was significantly greater in AAV-GFP-ΔJunD-treated BDL rats compared with all other groups. Daily average urine sodium concentration was significantly lower in AAV-GFP-ΔJunD-treated BDL rats than the other groups, although average daily sodium excretion was not different among the groups. SON expression of ΔJunD produced a diuresis in BDL rats that may be related to decreased circulating levels of vasopressin or oxytocin. These findings support the view that ΔFosB expression in SON magnocellular secretory cells contribute to dilutional hyponatremia in BDL rats.

Topics: Animals; Cholestasis; Disease Models, Animal; Green Fluorescent Proteins; Hyponatremia; Ligation; Liver Cirrhosis; Male; Oxytocin; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Supraoptic Nucleus; Vasopressins; Water-Electrolyte Balance

The aquaporin (AQP) water channel plays an important role in the regulation of water. AQP2 is expressed in the collection duct of the kidney, serving as the final channel that helps to regulate water excretion in the kidneys and affecting the regulation of water and hyponatremia in cirrhotic patients. So far, research on aquaporin expression in cirrhosis has had various results. The purpose of this study is to investigate the factors that affect the regulation of expression of AQP in patients with cirrhosis. The study comprised 81 cirrhosis patients and 18 control subjects. In each group, 24-h urine was collected and nitric oxide and vasopressin levels were measured in the blood. The amount of urinary AQP was measured by Western blot. In this study, the positivity rate and amount of expression of AQP was higher in the cirrhotic group than that of the control group. AQP expression in urine was also compared between the groups with use of diuretics and the groups with no use of diuretics. A 57.4% positivity was observed with the former, whereas a 51.5% was seen in the latter. No significance was found between the groups (P = 0.581). Expression of AQP in compensated cirrhotic patients is significantly higher than decompensated cirrhotic patients and is especially higher in cirrhotic patients with ascites than with no ascites. There is no relationship between the concentration of vasopressin and expression of AQP. Concentration of serum NOx is higher in cirrhotic patients than the control group and there is a positive association between the concentration of serum nitric oxide and AQP in urine. In conclusion, expression of AQP is increased in cirrhotic patients and is significantly higher in patients with ascites. There is a positive association between the expression of AQP and concentration of serum nitric oxide.

Topics: Adult; Aged; Aquaporin 2; Biopsy; Female; Hepatic Encephalopathy; Humans; Liver; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Multivariate Analysis; Nitric Oxide; Vasopressins; Water-Electrolyte Balance

Topics: Humans; Hyponatremia; Liver Cirrhosis; Prognosis; Severity of Illness Index; Vasopressins

Water retention in advanced cirrhosis and ascites may involve disturbances in renal distal tubular function and in the vasopressin system.. Twelve patients with Child B cirrhosis and ascites were compared with 11 patients with Child C cirrhosis and ascites. The subjects were studied during a 400 ml/h oral water load.. Child C patients had a lower baseline glomerular filtration rate (32 vs 63 ml/min, P<0.001) and a lower urinary flow rate (V(u)) (0.86 vs 1.95 ml/min, P<0.001) than the Child B patients. However, the free water clearance (C(H2O)) did not differ (-0.60 vs -0.21 ml/min, P=0.20). After the water loading, plasma vasopressin (AVP) decreased significantly in both the groups (P<0.05). The Child B patients had increased V(u) (1.95-3.24 ml/min, P<0.001) and C(H2O) (-0.21-1.21 ml/min, P<0.01) and distal fractional water excretion (10.5 vs 0% in Child C, P=0.01) and aquaporin-2 (AQP2) (P<0.058) after water loading. In contrast, the Child C patients did not have increased V(u) and C(H2O) in response to the water and the decrease in AVP. Furthermore, the markers of distal tubular water regulation, AQP2 excretion and distal fractional water excretion, were unaltered.. In Child C cirrhosis, ascites and mild hyponatraemia, there is an impaired ability to excrete solute-free water. The patients are characterised by a low glomerular filtration rate, a low distal tubular flow and an inability to increase free water clearance during water loading. This may be related to a vasopressin-independent production of AQP2.

Topics: Ascites; Body Water; Diuresis; Female; Humans; Kidney Tubules, Distal; Liver Cirrhosis; Male; Middle Aged; Severity of Illness Index; Vasopressins; Water-Electrolyte Imbalance

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.. 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.. 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.. In cirrhotic rats, chronic thalidomide treatment improves the portal-systemic collateral vascular responsiveness to AVP, which was partly related to VEGF inhibition.

Topics: Animals; Bile Ducts; Collateral Circulation; Liver Cirrhosis; Male; Portal System; Rats; Rats, Sprague-Dawley; Thalidomide; Vasopressins

Increased extracellular fluid volume (ECF) characterizes compensated cirrhosis. To identify the mechanisms of fluid retention in cirrhosis through clearance methods, 10 control and 10 preascitic rats with CCl(4)-induced cirrhosis were studied following i.v. loading with 1 ml 5% glucose solution. Glomerular filtration rate and renal plasma flow were evaluated through inulin and para-aminohippurate clearances; water and electrolyte handling was assessed measuring urine and plasma osmolarity, electrolyte excretions, and tubular solute-free water reabsorption (TFWR = osmolar clearance minus urinary output); ECF was assessed through hormonal status determination. After water loading, cirrhotic rats had increased ECF (lower plasma renin activity and aldosterone and higher atrial natriuretic peptide levels, all P<0.03), solute-free water retention (increased TFWR and decreased plasma osmolarity, all P<0.05), reduced absolute and fractional sodium excretions (P<0.05). Cirrhotic rats showed sodium retention in the medullary thick ascending limb of Henle's loop (i.e. increased values of TFWR for any given value of osmolar clearance). Trans-tubular potassium gradient in medullary collecting duct was similar in the two groups (P=0.55), ruling out aldosterone-dependent sodium retention and potassium hyper-secretion. In experimental preascitic cirrhosis NaCl retention in the ascending limb of Henle's loop increases medullary interstitial tonicity leading to vasopressin-independent water back-diffusion in thin descending limb of Henle's loop and collecting duct.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Extracellular Fluid; Glomerular Filtration Rate; Kidney; Kidney Tubules, Distal; Liver Cirrhosis; Loop of Henle; Male; Osmolar Concentration; Potassium; Rats; Rats, Wistar; Renin; Sodium; Vasopressins; Water; Water-Electrolyte Imbalance

Impaired urinary dilution leading to water retention and hyponatremia may occur in patients with cardiac failure, cirrhosis, pregnancy, hypothyroidism, glucocorticoid and mineralocorticoid deficiency. The mechanisms for these defects predominantly involve the non-osmotic stimulation of arginine vasopressin release with upregulation of aquaporin 2 water channel expression and trafficking to the apical membrane of the principal cells of the collecting duct. These perturbations are reversed by V2 vasopressin receptor antagonists. In contrast, urinary concentration defects leading to polyuria are vasopressin-resistant. They may involve several factors, such as impaired counter-current concentration secondary to downregulation of Na-K-2Cl co-transporter. Vasopressin-resistant downregulation of aquaporin 2 expression has also been described as a factor in impaired urinary concentration.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Aquaporin 2; Arginine Vasopressin; Blood Volume; Female; Heart Failure; Homeostasis; Humans; Hyponatremia; Liver Cirrhosis; Models, Biological; Polyuria; Pregnancy; Pregnancy Complications; Pressoreceptors; Sodium-Potassium-Chloride Symporters; Urine; Vasopressins; Water-Electrolyte Balance

Vasodilation due to impaired vascular tone is common in liver failure. Vasoconstrictor drugs are almost always required during the anhepatic phase of a liver transplant to maintain blood pressure unless venovenous bypass is employed. Arginine-vasopressin can be used as a vasoconstrictor instead of or in addition to norepinephrine for this purpose, but the effect of vasopressin on the portal vein pressure and flow in this setting is unknown. Portal vein pressure, portal vein blood flow, hemodynamic variables, and plasma vasopressin levels were measured in 16 patients during liver transplantation after ligation of the hepatic artery before and after a vasopressin infusion of 3.8 +/- 1.1 units/hour. Measurements were performed on the native liver prior to caval clamping. After vasopressin infusion, the portal vein pressure decreased significantly from 24.0 +/- 6.5 to 21.5 +/- 7.4 mm Hg [mean +/- standard deviation (SD), P = 0.006]. The portal vein blood flow also decreased (from 1.01 +/- 0.53 to 0.76 +/- 0.53 L/minute, mean +/- SD, P < 0.0001), as did the portal vein blood flow to cardiac output ratio (from 0.14 +/- 0.06 to 0.10 +/- 0.07, mean +/- SD, P < 0.0001). In conclusion, vasopressin significantly decreased portal vein pressure and flow of the native liver without decreasing cardiac output or intestinal perfusion in patients undergoing liver transplantations.

Topics: Aged; Arginine Vasopressin; Blood Flow Velocity; Blood Pressure; Enzyme-Linked Immunosorbent Assay; Female; Humans; Liver; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Portal Vein; Treatment Outcome; Vasopressins

Preascitic cirrhosis is characterised by subtle renal sodium retention. Calcium inhibits Na(+)-K(+)-2Cl(-) cotransport in the Henle's loop and could potentially correct sodium-handling abnormalities at that site.. To investigate the effects of calcium infusion on sodium handling in 10 patients with preascitic cirrhosis and nine healthy controls after 1 week of sodium loading of 200 mmol sodium/day.. All patients underwent a 3 h supine determination of inulin, para-aminohippurate, lithium and free-water clearances, absolute and fractional excretions of sodium, potassium and calcium and plasma concentrations of renin, aldosterone, norepinephrine and vasopressin. The same were repeated over a further 3 h supine period including 60 min intravenous infusion of 33 mg/min calcium gluconate.. After sodium loading, the 24 h urinary sodium excretion in patients with cirrhosis was lower than that in controls (p<0.03). Calcium infusion significantly decreased plasma norepinephrine levels (p<0.03), and induced greater increases in fractional delivery of sodium to the Henle's loop (p<0.5) in those with cirrhosis than in controls. This was associated with a decreased fractional reabsorption of sodium beyond the proximal tubule (p<0.03), resulting in greater urinary volume, sodium excretion and free-water clearance in those with cirrhosis than in controls (all with p<0.05). Because the aldosterone-driven potassium secretion, as assessed by the computation of tubular-capillary gradient of [K(+)] in the collecting duct, was similar in the two groups and unaffected by calcium, sodium retention must have occurred in the Henle's loop in those with cirrhosis.. Calcium is natriuretic in patients with preascitic cirrhosis; it also decreases norepinephrine release, which could be responsible for decreased reabsorption of sodium in the Henle's loop.

Topics: Absorption; Adrenergic alpha-Agonists; Aldosterone; Calcium; Female; Humans; Infusions, Intravenous; Kidney Tubules, Proximal; Liver Cirrhosis; Loop of Henle; Male; Metabolic Clearance Rate; Middle Aged; Norepinephrine; Potassium; Renin; Sodium; Supine Position; Vasopressins

Arginine vasopressin (AVP) exerts a constrictive effect on the portal-systemic collaterals of non-cirrhotic portal hypertensive rats, but its effect on cirrhotic rats is unknown. The aim of this study was to investigate the response of AVP and the modulatory roles of nitric oxide and prostaglandin on collaterals of common bile duct-ligated (BDL) cirrhotic rats.. The collateral vascular responsiveness to graded concentrations of AVP (10(-10) - 3 x 10(-7) M) was tested by an in situ collateral perfusion system pretreated with Nomega-nitro-L-arginine (L-NNA, 100 microM), indomethacin (INDO, 10 microM), or both. The collateral responses to AVP with the pretreatment of a vasopressin V1 receptor antagonist d(CH2)5Tyr(Me) arginine vasopressin or a V2 receptor agonist 1-desamino-8-D-arginine vasopressin (DDAVP, 10(-10) - 3 x 10(-7) M) were also evaluated.. The perfusion pressure of collaterals was significantly increased by AVP, and this effect was inhibited by the addition of the V1 receptor antagonist. DDAVP had no effect on the collaterals. Incubation with L-NNA or L-NNA plus INDO, but not INDO alone, significantly potentiated the constrictive effects of AVP. The constrictive effect of AVP in the combination group was similar to that in the L-NNA alone group.. The results show that AVP produces a direct vasoconstrictive effect on the portal-systemic collaterals of BDL cirrhotic rats. The constrictive effect of AVP is mediated by the vasopressin V1, instead of V2, receptors. Nitric oxide may play a more important role than prostaglandin in modulating the collateral vascular response to AVP in BDL cirrhotic rats.

Topics: Animals; Collateral Circulation; Disease Models, Animal; Liver Circulation; Liver Cirrhosis; Male; Nitric Oxide; Portal System; Probability; Prostaglandins; Random Allocation; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Vasopressins

Topics: Esophageal and Gastric Varices; Evidence-Based Medicine; Gastrointestinal Hemorrhage; Hemostasis, Endoscopic; Hemostatics; Humans; Hypertension, Portal; Liver Cirrhosis; Meta-Analysis as Topic; Sclerotherapy; Somatostatin; Vasopressins

Water retention is a major clinical problem in patients with liver cirrhosis. Recent research suggests that renal aquaporins may be pathophysiologically involved in this condition. The aim of the present cross sectional study of patients with liver cirrhosis was to determine if 24 hour urinary excretion of renal aquaporin 2 (AQP2) differed from that of healthy control subjects and if such excretion was related to the severity of liver disease and to the patient's water balance.. Twenty four hour urinary excretion of AQP2 and free water clearance were measured in 33 stable cirrhosis patients on usual medication and in eight healthy subjects. AQP2 excretion, quantitated by immunoblotting, was eight times higher in cirrhosis patients than in controls (0.167 (0.270) U/day v 0.021 (0.017); p<0.05). Stratification according to clinical manifestations (Child- Pugh classes) revealed that it increased with the clinical severity of cirrhosis (class A 0.04 (0.04); class B 0.09 (0.16); class C 0.31 (0.35); p<0.05) but was not related to liver function, as measured by galactose elimination capacity. Excretion correlated inversely with free water clearance (rho=-0.57, p<0.01). It was higher in patients with oesophagogastric varices but not in those with ascites. Plasma vasopressin concentrations were not related to AQP2 excretion and there was no relation to dose or type of diuretic treatment.. Urinary AQP2 excretion was increased in patients with cirrhosis. Moreover, urinary AQP2 excretion increased with severity of cirrhosis in parallel with impairment of free water clearance. This suggests a functional association between increased AQP2 excretion and increased renal reabsorption of water in cirrhosis.

Topics: Adult; Aged; Aged, 80 and over; Aquaporin 2; Aquaporin 6; Aquaporins; Creatinine; Cross-Sectional Studies; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Osmolar Concentration; Vasopressins; Water-Electrolyte Balance

Our previous studies indicated that in the human paraventricular (PVN) and supraoptic (SON) nuclei, tyrosine hydroxylase (TH)--the first and rate-limiting enzyme in catecholamine synthesis--is localized mainly in magnocellular neurons and that antemortem factors regulate its expression. The purpose of the present study was to investigate the distribution of TH-immunoreactive (TH-IR) perikarya of the hypothalami of a large sample of well-documented adult subjects without neurological, psychiatric or endocrinological disease in order to identify factors that could regulate the expression of TH in the human neurosecretory neurons. Our material consisted of the hypothalami of 38 subjects studied immunohistochemically for TH using the peroxidase-antiperoxidase method. Striking individual differences were observed among the subjects studied concerning the number and distribution of TH-IR perikarya within the PVN and SON. These differences were evident throughout the entire rostrocaudal length of the hypothalamus and appeared to be related neither to the age or sex of the subjects nor to the postmortem interval or staining procedures. In the sample studied, a large number of TH-IR perikarya were observed specifically in all subjects that had suffered from right-sided heart failure due to pulmonary hypertension, liver cirrhosis or dehydration. In all the above illnesses, increased production and secretion of vasopressin (VP) are reported to occur due to a decrease in 'effective' blood volume or to osmotic stimulation. We conclude that somatic illnesses leading to prolonged osmotic or nonosmotic stimulation of VP release may induce increased expression of TH immunoreactivity in the human neurosecretory neurons related to neuronal activation.

Topics: Adult; Aged; Aged, 80 and over; Cardiac Output, Low; Dehydration; Disease; Female; Humans; Hypertension, Pulmonary; Immunohistochemistry; Liver Cirrhosis; Male; Middle Aged; Neurons; Osmosis; Paraventricular Hypothalamic Nucleus; Supraoptic Nucleus; Time Factors; Tyrosine 3-Monooxygenase; Vasopressins

Nitric oxide has been proposed as a mediator of hyperdynamic circulation in cirrhosis. Endotoxin and cytokines induce the synthesis of nitric oxide. The aim of this study was to investigate the relationship between endotoxemia, cytokines, and nitric oxide in patients with cirrhosis, and to correlate these findings with clinical, biochemical, and hemodynamic parameters.. Clinical, biochemical, and hemodynamic parameters were assessed in 66 patients with cirrhosis and 15 controls. Levels of antidiuretic hormone, plasma renin activity, aldosterone, interferon gamma, interleukin-1, interleukin-6, tumor necrosis factor alpha, endotoxin, and nitrates-nitrites were determined.. Mean arterial pressure was lower and interleukin-6, tumor necrosis factor alpha, nitrites-nitrates levels, and endotoxin positivity rates were higher in cirrhotics than in controls (p < 0.005). Mean arterial pressure decreased and interleukin-6 levels increased with worsening of Child score (p < 0.005). Patients with ascites had higher levels of interleukin-6, tumor necrosis factor alpha, and nitrates-nitrites than patients without ascites (p < 0.01). Elevated levels of interleukin-6 were found in patients with encephalopathy grade I, compared with patients without (p < 0.001); this association was independent of the severity of liver disease. In patients with low mean arterial pressure, interleukin-6 levels were higher than in patients with high mean arterial pressure (p = 0.001), whereas tumor necrosis factor alpha and nitrates-nitrites levels were not different. By multivariate analysis, high interleukin-6 levels showed independent associations with the presence of ascites, encephalopathy, and low mean arterial pressure. Only interleukin-6 levels had significant correlations with Child score, plasma renin activity, serum and urinary sodium, and mean arterial pressure (r > or = 0.4, p < 0.005).. Although the activity of the nitric oxide pathway is increased in patients with cirrhosis and might contribute to the hemodynamic alteration, other factors are involved. Interleukin-6, possibly through nitric oxide-independent mechanisms, also might play a role in the vasodilatation of cirrhosis and the pathogenesis of hepatic encephalopathy.

Topics: Aged; Aldosterone; Ascites; Blood Pressure; Endotoxins; Female; Hepatic Encephalopathy; Humans; Interferon-gamma; Interleukin-1; Interleukin-6; Liver Cirrhosis; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Renin; Tumor Necrosis Factor-alpha; Vasopressins

The pathogenesis of impaired water excretion in liver cirrhosis has not been fully elucidated.. We induced an intravenous water overload of 20 ml/kg body weight in 10 cirrhotics without ascites (CLC), 11 cirrhotics with ascites (DLC), and 10 normal subjects (N) and investigated the relationship of plasma levels of substance P (SP), norepinephrine (NE), and antidiuretic hormone (ADH) to impaired water excretion.. Free water clearance (CH2O) was lower in DLC (mean, 2.7 ml/min) than in N (8.3 ml/min; P < 0.001) and CLC (6.9 ml/min; P < 0.001). In DLC the creatinine clearance (CCr), maximal urine flow rate/CCr, (CH2O + CNa)/CCr, and mean arterial pressure (MAP) were significantly lower than in N and CLC. There was a progressive increase in basal SP, from lowest in N to CLC, to highest in DLC. Basal NE increased in CLC and DLC. Basal ADH did not differ among N, CLC, and DLC. In cirrhotics CH2O was correlated positively with serum albumin and cholinesterase and negatively with the retention rate of indocyanine green at 15 min. Basal SP was negatively correlated with CH2O (r= -0.71: P < 0.001) and MAP (r= -0.56; P < 0.005). Basal NE was correlated positively with basal SP (r= 0.67, P < 0.01 ).. Decreased CH2O is closely related to the severity of the liver disturbance. Decreased CCr and reduced delivery of filtrate to the ascending limb of the loop of Henle secondary to an increased sodium reabsorption in the proximal tubule may play an important role in the impairment of water excretion. The increase in SP, which has a potent vasodilatory action, and the associated enhanced activity of the sympathetic nervous system may be responsible for the mild or moderate impairment of water excretion in the absence of nonosmotic hypersecretion of ADH in cirrhotics with ascites.

Topics: Adult; Case-Control Studies; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Norepinephrine; Severity of Illness Index; Substance P; Vasopressins; Water

The effects of the acute administration of arterial vasoconstrictors on renal plasma flow (RPF) and urinary sodium excretion (UNaV) in cirrhotic patients with ascites with or without hepatorenal syndrome (HRS) are still controversial. As a consequence, vasoconstrictors are not actually used in the treatment of renal sodium retention or HRS in these patients, regardless of the several lines of evidence suggesting that these renal functional abnormalities are related to a marked arterial vasodilation. The lack of an orally available effective arterial vasoconstrictor probably represents a further reason for this omission. Consequently, the present study was made to evaluate the acute effects of the oral administration of midodrine, an orally available -mimetic drug, on systemic and renal hemodynamics and on UNaV in cirrhotic patients with ascites. Mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), systemic vascular resistance (SVR), left forearm blood flow (LFBF), left leg blood flow (LLBF), RPF, glomerular filtration rate (GFR), UNaV, plasma renin activity (PRA), plasma concentration of antidiuretic hormone (ADH), and the serum levels of nitrite and nitrate (NOx) were evaluated in 25 cirrhotic patients with ascites (17 without HRS and 8 with type 2 HRS) before and during the 6 hours following the oral administration of 15 mg of midodrine. During the first 3 hours after the drug administration, a significant increase in MAP (89.6 +/- 1.7 vs. 81.80 +/- 1.3 mm Hg; P < .0001) and SVR (1, 313.9 +/- 44.4 vs. 1,121.2 +/- 60.1 dyn . sec . cm-5; P < .0001) accompanied by a decrease in HR (69 +/- 2 vs. 77 +/- 3 bpm; P < .005) and CI (2,932.7 +/- 131.4 vs. 3,152.5 +/- 131.4 mL . min-1 . m2 BSA; P < .0025) was observed in patients without HRS. No change was observed in LFBF and LLBF. The improvement in systemic hemodynamics, which was also maintained during the the 3- to 6-hour period after midodrine administration, was accompanied by a significant increase in RPF (541.5 +/- 43.1 vs. 385.7 +/- 39.9 mL . min-1; P < .005), GFR (93.1 +/- 6.5 vs. 77.0 +/- 6.7 mL . min-1; P < .025), and UNaV (92.7 +/- 16.4 vs. 72.2 +/- 10.7 microEq . min-1; P < .025). In addition, a decrease in PRA (5.33 +/- 1.47 vs. 7.74 +/- 2.17 ng . mL-1 . h; P < .05), ADH (1.4 +/- 0.2 vs. 1.7 +/- 0.2 pg . mL-1; P < .05), and NOx (33.4 +/- 5.0 vs. 49.3 +/- 7.3 micromol-1; P < .05) was found. In patients with HRS, the effects of the drug on the systemic hemodynamics was smaller and shorte

Topics: Administration, Oral; Adrenergic alpha-Agonists; Ascites; Blood Pressure; Cardiac Output; Female; Glomerular Filtration Rate; Heart Rate; Hemodynamics; Humans; Kidney; Kidney Function Tests; Liver Cirrhosis; Male; Middle Aged; Midodrine; Nitrates; Nitrites; Regional Blood Flow; Renal Circulation; Renin; Vascular Resistance; Vasoconstriction; Vasopressins

To investigate a possible relationship between the renal production of endothelin and the presence of renal dysfunction and activation of vasoactive systems in cirrhosis, the urinary excretion and the circulating plasma levels of immunoreactive endothelin (irET) and the plasma levels of vasoactive hormones were measured in 19 healthy subjects, 12 cirrhotic patients without ascites and 39 patients with ascites and different degrees of renal dysfunction.. The urinary excretion and the circulating levels of irET were assessed after 5 days on a 40 mEq sodium diet and off diuretics. Renal function parameters and the plasma levels of vasoactive hormones were also measured.. Patients with and without ascites had similar values of urinary irET as compared with healthy subjects (30+/-3, 31+/-3 and 29+/-2 ng/day, respectively, p>0.10). By contrast, patients with ascites had higher circulating levels of irET (15+/-1.2 pg/ml) than patients without ascites and healthy subjects (11+/-1.6 and 5+/-0.4 pg/ml, p<0.01). In patients with cirrhosis, no correlation was found between urinary irET and circulating irET. Moreover, urinary irET did not correlate with liver tests, serum and urine sodium, glomerular filtration rate or vasoactive substances. Patients with hepatorenal syndrome had similar urinary irET to patients with ascites without hepatorenal syndrome.. Urinary excretion of irET is not increased in cirrhotic patients with ascites and does not correlate with abnormalities in renal function.

Topics: Adult; Aldosterone; Ascites; Atrial Natriuretic Factor; Endothelins; Female; Hepatorenal Syndrome; Humans; Liver Cirrhosis; Male; Middle Aged; Norepinephrine; Renin; Vasopressins

Topics: Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hormone Antagonists; Humans; Liver Cirrhosis; Liver Transplantation; Portasystemic Shunt, Surgical; Sclerotherapy; Somatostatin; Vasopressins

It is well known that sodium retention occurs in a significant proportion of patients with cirrhosis despite normal supine plasma levels of renin, aldosterone (ALDO), and norepinephrine (NE). The current study was performed to assess whether this subset of patients also present normal activity of the renin-aldosterone and sympathetic nervous systems during upright posture in sitting position and moderate physical exercise. Nine healthy controls, 14 patients with compensated cirrhosis and 10 patients with cirrhosis, ascites, sodium retention, and normal supine plasma renin activity (PRA) and ALDO and NE concentration were sequentially studied after 60 minutes in supine rest, 30 minutes in sitting position, and 30 minutes of cycloergometric exercise (3-METs). Sitting position and exercise were associated with similar stimulation of the renin-aldosterone and sympathetic nervous systems in the three groups of subjects. Consequently, cirrhotic patients with ascites showed values of PRA and plasma concentration of ALDO and NE similar to healthy subjects and patients with compensated cirrhosis during supine rest (renin: 1.4 +/- 0.3, 0.8 +/- 0.2, and 0.8 +/- 0.3 ng/mL; aldosterone: 24.3 +/- 4.7, 20.2 +/- 3.9 and 21.4 +/- 3.4 ng/dL; norepinephrine: 252 +/- 23, 250 +/- 16, and 255 +/- 23 pg/mL), sitting position (renin: 2.1 +/- 0.5, 1.1 +/- 0.3, and 1.6 +/- 0.4; aldosterone: 32.2 +/- 7.3, 23.7 +/- 5.3, and 26.2 +/- 4.5; norepinephrine: 356 +/- 38, 401 +/- 63, and 420 +/- 35), and exercise (renin: 2.9 +/- 0.8, 1.6 +/- 0.4, and 2.2 +/- 0.5; aldosterone: 43 +/- 6.4, 34.9 +/- 8.5, and 38.2 +/- 5.3; norepinephrine: 481 +/- 35, 499 +/- 54, and 534 +/- 48).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldosterone; Atrial Natriuretic Factor; Exercise; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Natriuresis; Neurosecretory Systems; Norepinephrine; Posture; Renin; Sodium; Supine Position; Vasopressins

Torsade de pointes is an unusual life-threatening ventricular arrhythmia that has been associated with vasopressin, neuroleptic drugs, and electrolyte imbalances, including hypokalemia and hypomagnesemia. Over a 9-month period, we observed torsade de pointes in three patients with cirrhosis and bleeding esophageal varices who did not have prior cardiac disease. All had received endoscopic sclerotherapy and continuous infusions of vasopressin and nitroglycerin. For sedation, two patients received haloperidol and one droperidol. In addition, two patients had either hypokalemia or hypomagnesemia. In all three patients, there was prolongation of the electrocardiographic QT interval and a "long-short" initiating sequence followed by ventricular tachycardia with torsade de pointes morphology. All were successfully cardioverted; there was one late death due to aspiration and septicemia. We conclude that cirrhotics with variceal hemorrhage may be at increased risk of developing this arrhythmia in the setting of treatment with vasopressin, sedation with neuroleptic drugs, and electrolyte abnormalities. We urge close monitoring of these patients for cardiac arrhythmia and recommend that neuroleptics be used cautiously, if at all.

Topics: Adult; Antipsychotic Agents; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Torsades de Pointes; Vasopressins; Water-Electrolyte Imbalance

Topics: Catheterization; Embolization, Therapeutic; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostatics; Humans; Liver Cirrhosis; Sclerotherapy; Somatostatin; Vasopressins

A problem in pharmacotherapy for bleeding varices in portal hypertension is non-responders. The aim of this study was to elucidate the features of hemodynamic response to vasopressin in the gastroesophageal collateral vein in patients with esophageal varices.. Flow velocity in the portal and the collateral left gastric vein was measured with an echo-Doppler flowmeter before and during infusion of vasopressin, 0.2 U/min, in 41 patients with cirrhosis and esophageal varices.. The decrease in flow velocity in the left gastric vein with vasopressin (-29 +/- 25%) was significantly smaller than that in the portal vein (-56 +/- 20%). There was no or only minimal change in flow velocity in the left gastric vein in 39% of the patients, especially in those with large-size varices. In 28 patients examined by portal catheterization, changes in flow velocity in the left gastric vein were correlated with portal pressure, and portal pressure in non-responders was significantly higher than that in responders (non-responders: 363 +/- 49, responders: 312 +/- 41 mmH2O, p < 0.05).. It was concluded that hepatofugal blood flow in the gastroesophageal collateral is not readily reduced by vasopressin. However, as the study was performed in a stable condition without variceal bleeding, whether these hemodynamic features will apply during acute variceal bleeding in patients who are known to have a poor hemodynamic response to vasopressin remains to be elucidated.

Topics: Aged; Blood Flow Velocity; Collateral Circulation; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Hemodynamics; Hemostatics; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Retrospective Studies; Stomach; Ultrasonography, Doppler, Duplex; Ultrasonography, Doppler, Pulsed; Vasopressins; Veins

We evaluated the dynamic response of renin, aldosterone, and vasopressin to intravenous water loading (20 ml 5% glucose/kg b.w.) in 12 children (aged 7-18 years) with postinflammatory liver cirrhosis after hepatitis B virus (HBV) infection. All of the patients had early-stage liver cirrhosis; according to Child's classification, nine patients had group A; three, group B cirrhosis. A group of 17 children with chronic persistent hepatitis served as the control. The diagnoses were confirmed in all of the patients by liver biopsy. The patients followed a diet containing 3 mmol NaCl/kg/day, maximum 100 mmol per day for 6 days. Water loading was performed in recumbency over approximately 45 min. Renin, aldosterone, and vasopressin, assayed by radioimmunoassay (RIA), were determined before, 1 h, and 5 h after starting the water load. Prestudy hormone levels were within normal range in both groups. Renin and aldosterone concentration change patterns were similar in both groups and characterized by suppression of hormone activity caused by central volume expansion and recovery to prestudy levels after 5 h. However, the pattern of change of vasopressin concentrations differed in the control and study groups. In contrast to that of the controls, volume expansion did not suppress vasopressin in the group with liver cirrhosis. We conclude that failure to suppress vasopressin activity after central volume expansion may be one of the early mechanisms responsible for water-electrolyte imbalance in liver cirrhosis in children.

Topics: Adolescent; Aldosterone; Child; Female; Glucose; Hepatitis B; Humans; Infusions, Intravenous; Liver Cirrhosis; Male; Potassium; Renin; Renin-Angiotensin System; Sodium; Vasopressins; Water; Water-Electrolyte Imbalance

Hepatic venous catheterization is widely used to assess portal pressure. However, it remains unclear whether wedged hepatic venous pressure is a close indicator of portal venous pressure during vasoactive drug administration in nonalcoholic cirrhosis. To address this issue, we analyzed the data from our previous published studies. Forty patients with nonalcoholic cirrhosis (HBV infection in five, HCV infection in 28, and cryptogenic in seven) were available in this analysis. A vasoconstrictor (N = 14), vasodilator (N = 10), or combination (N = 16) was administered. The agreement of the changes between portal and wedged hepatic venous pressures during pharmacological manipulation was assessed by an intraclass correlation coefficient. The intraclass correlation coefficient in each subgroup was more than 0.60 (0.62 in vasoconstrictor group, 0.87 in vasodilator group, and 0.73 in combination group). When the analysis was performed according to the cause of liver disease, the values were 0.67 in HBV infection, 0.73 in HCV infection, and 0.74 in cryptogenic cirrhosis. These results suggest that wedged hepatic venous pressure reflects portal venous pressure during vasoactive drug administration in patients with nonalcoholic cirrhosis.

Topics: Female; Hepatic Veins; Hepatitis B; Hepatitis C; Humans; Liver Cirrhosis; Male; Middle Aged; Nitroglycerin; Portal Pressure; Vasoconstrictor Agents; Vasodilator Agents; Vasopressins; Venous Pressure

To evaluate the possible role of vagal impairment in the disturbances of urinary sodium and water excretion observed in cirrhosis.. Standard cardiovascular reflex tests were used to assess Autonomic function in 11 cirrhotic patients, and the response to an acute intravenous water load was determined. Changes in plasma noradrenaline, antidiuretic hormone, renin, and atrial natriuretic peptide also were evaluated.. Patients with vagal dysfunction were shown to have significantly impaired urinary sodium and water excretion, compared with those whose cardiovascular tests were normal (5-h urinary sodium excretion, 32.3 +/- 9.0 vs. 69.4 +/- 12.7 mmol, p < 0.05; % water load excreted at 5 h, 67.8 +/- 10.5 vs. 109.2 +/- 3.67%, p < 0.008). This was associated with higher circulating noradrenaline, renin, and antidiuretic hormone levels after the water load in the vagal dysfunction group. Urinary sodium excretion correlated with the heart rate variation on deep breathing (r = 0.74, p < 0.013) and the heart rate response to atropine (r = 0.75, p < 0.020); the % water load excreted correlated with the number of abnormal cardiovascular tests in each patient (rS = 0.67, p < 0.02). Although patients with vagal abnormalities had worse liver function, urinary sodium and water excretion correlated better with parasympathetic tests than with standard parameters of hepatic function.. The presence of vagal impairment in cirrhosis appears to be associated with impaired urinary sodium and water excretion, as well as disturbances in circulating vasoactive hormones. These findings could be due to an afferent defect resulting in diminished inhibitory input from intrathoracic volume and arterial baroreceptors, although a confounding effect of worse hepatic function in patients with vagal impairment cannot be excluded.

Topics: Atrial Natriuretic Factor; Diuresis; Epinephrine; Female; Heart Rate; Humans; Liver Cirrhosis; Liver Cirrhosis, Biliary; Male; Middle Aged; Renin; Sodium; Vagus Nerve; Vasopressins

We studied the effects of the combination of nitroglycerin and vasopressin on portohepatic hemodynamics, hepatic function, and blood gases in nine patients with cirrhosis and portal hypertension. Vasopressin infusion at a dose of 0.4 U/min caused a significant fall in portal pressure, which is evaluated by portal venous pressure gradient (-34%, p less than 0.01), associated with a decrease in hepatic perfusion (-33%, p less than 0.01) and intrinsic clearance (-20%, p less than 0.01) after 30 min. The arterial oxygenation, however, was not modified (paO2; from 73 +/- 8 to 72 +/- 7 mm Hg, NS). Nitroglycerin infusion at a dose of 100 micrograms/min was then administered for 20 min. The addition of nitroglycerin produced a further reduction in free portal venous pressure (-12%, p less than 0.01), but this was not associated with a significant improvement in both hepatic perfusion (+16%, NS) and intrinsic clearance (-7%, NS). In addition, there was a significant fall in arterial oxygenation (paO2; from 72 +/- 7 to 59 +/- 5 mm Hg, p less than 0.01). We conclude that the addition of nitroglycerin to vasopressin has a beneficial effect on free portal venous pressure, but does not have hepatic benefit. Moreover, sufficient care must be taken, when treating portal hypertension with this combination, to avoid arterial hypoxemia.

Topics: Aged; Catheterization, Peripheral; Child; Drug Therapy, Combination; Esophageal and Gastric Varices; Female; Hemodynamics; Humans; Hypertension, Portal; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Nitroglycerin; Oxygen; Vasopressins

In patients with portal hypertension, bleeding from the gastric mucosa is common, and is often treated with vasopressin (VP). VP reduces the portal pressure by contracting the arterioles of the abdominal organs. In normal rats, VP reduces the gastric mucosal blood flow (GMBF). However, it is not sure whether the reduction of the portal pressure by VP actually reduces the GMBF in patients with portal hypertension. Here, we studied the effects of VP on the GMBF of 24 patients with portal hypertension resulting from cirrhosis. The ICG15 test was done for 20 of the patients. We measured the GMBF of the antrum and body of the stomach using a laser Doppler flowmeter (Peliflux PF 2) connected with a gastrofiberscope without VP on one day and about 10 min after the start of administration of VP (0.4 U/min, i.v.) on another day. Unexpectedly, the GMBF was increased with VP in 14 of 22 patients at the antrum and in 19 of 24 patients at the body of the stomach. In the body of the stomach, there was correlation between the increase in the GMBF caused by VP and the results of the ICG15 test. A high ICG15 reflects high portal pressure, so this finding indicates that in high portal pressure, the GMBF is increased by VP, and in low portal pressure, the GMBF is decreased by VP.

Topics: Animals; Blood Flow Velocity; Gastric Mucosa; Humans; Hypertension, Portal; Liver Cirrhosis; Rats; Rats, Inbred Strains; Vasopressins

Endogenous opioids may be involved in the pathogenesis of ascites and edema in patients with liver cirrhosis. We administered the opioid antagonist naloxone (5 mg bolus followed by a 0.06 mg/min infusion) to eight male patients with alcoholic cirrhosis and ascites and to five healthy age- and sex-matched control subjects and determined the effects of naloxone on water and electrolyte excretion after a nonsustained water load (20 ml/kg). In comparison with saline vehicle infusion carried out in the same subjects, naloxone administration resulted in a 50% increase in urine output and creatinine clearance and twofold increases in sodium and potassium excretion in patients with cirrhosis. Fractional sodium and potassium excretion, minimal urinary osmolality, plasma vasopressin and aldosterone levels, arterial blood pressure, and heart rate were not affected by naloxone treatment. The diuretic effect of naloxone was not observed in control subjects. Plasma naloxone levels were about six times higher in patients with cirrhosis than in control subjects (probably because of impaired metabolism of the drug) but only a weak correlation was found between drug levels and the degree of diuresis observed. The diuretic effect of naloxone may be related to an increase in glomerular filtration rate, possibly in conjunction with altered tubular reabsorption.

Topics: Aged; Aldosterone; Ascites; Blood Pressure; Body Water; Creatine; Electrolytes; Glomerular Filtration Rate; Heart Rate; Humans; Liver Cirrhosis; Male; Middle Aged; Naloxone; Potassium; Sodium; Vasopressins; Water-Electrolyte Balance

It has been suggested that vasopressin given during hemorrhage may be less effective than when given during a stable state in a portal-hypertensive rat model. This study was designed to evaluate the hemodynamic response to vasopressin infusion in 25 HBsAg-positive cirrhotic patients. Nine patients had active variceal hemorrhage before vasopressin infusion, and the other 16 patients were in a stable condition at the time of infusion. The two groups of patients were similar in baseline values except that a higher heart rate was found in patients with hemorrhage (96 +/- 20 vs. 73 +/- 10 beats/min, mean +/- S.D., p less than 0.01). Thirty minutes after vasopressin infusion (0.66 units/min), hepatic venous pressure gradient significantly decreased in both bleeding and stable patients (from 21 +/- 9 to 18 +/- 9 mm Hg, p less than 0.05; and from 18 +/- 4 to 8 +/- 3 mm Hg, p less than 0.0001, respectively). However, the decrease of hepatic venous pressure gradient was less obvious in bleeding patients as compared with stable patients (4 +/- 3 vs. 9 +/- 2 mm Hg, p less than 0.0001). A significant reduction of hepatic venous pressure gradient after vasopressin infusion was found in five bleeding patients without shock (from a median of 16 mm Hg [range = 12 to 26] to 11 mm Hg [range = 6 to 18], p less than 0.05), but not in four bleeding patients with shock (from 28 [range = 15 to 36] to 25 [range = 18 to 33] mm Hg, p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Blood Pressure; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Heart Rate; Hepatitis B; Humans; Liver Circulation; Liver Cirrhosis; Male; Middle Aged; Vasopressins; Venous Pressure

Renal function and plasma antidiuretic hormone (ADH) levels were studied basally and after oral water load in four groups of subjects: 15 healthy controls (group I), 15 cirrhotics without ascites (group II), 15 cirrhotics with ascites (group III), and 10 decompensated cirrhotics with hyponatremia (group IV). Renal function and ADH levels were normal in group II. In groups III and IV water diuresis and fractional proximal sodium excretion were significantly decreased, whereas fractional distal sodium resorption and fractional excretion of potassium did not differ from those of controls. Basal ADH was significantly increased only in patients of group IV. In these patients ADH remained abnormally high after water loading. ADH did not correlate with water diuresis, plasma osmolality, mean arterial pressure, and plasma renin activity. We conclude that impaired water excretion in decompensated cirrhotics without hyponatremia cannot be ascribed to high serum levels of ADH. On the contrary, it seems to be related mainly to a reduced delivery of filtrate to the diluting segment of the nephron. In cirrhotic patients with hyponatremia high levels of ADH may play an additional role.

Topics: Adult; Female; Humans; Hyponatremia; Kidney; Liver Cirrhosis; Male; Middle Aged; Sodium; Vasopressins; Water

To assess vasopressin control of esophageal variceal bleeding, we investigated the effect of vasopressin on the left gastric venous flow, portal venous flow, superior mesenteric venous flow, and splenic venous flow in seven cirrhotic patients with esophageal varices, using a duplex system consisting of a real-time ultrasonograph and an echo-Doppler flowmeter. Infusion of vasopressin (0.3 U/min) significantly decreased the blood flow in the left gastric vein (-56%), portal trunk (-54%), superior mesenteric vein (-54%), and splenic vein (-56%) as a result of decrease of blood velocity in these vessels. Thus, vasopressin seems to control esophageal variceal bleeding, in part, by reducing blood velocity and blood flow in the left gastric vein following reduction of blood velocity and blood flow in the superior mesenteric vein and splenic vein.

Topics: Adult; Blood Flow Velocity; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Mesenteric Veins; Middle Aged; Portal Vein; Regional Blood Flow; Splenic Vein; Stomach; Ultrasonography; Vasopressins

Topics: Azygos Vein; Blood Flow Velocity; Esophageal and Gastric Varices; Humans; Liver Cirrhosis; Ultrasonography; Vasopressins

Topics: Atrial Natriuretic Factor; Humans; Liver Cirrhosis; Natriuresis; Vasopressins

Topics: Animals; Atrial Natriuretic Factor; Humans; Hypertension, Portal; Liver Cirrhosis; Liver Cirrhosis, Experimental; Natriuresis; Rats; Vasopressins

We evaluated a group of 21 cirrhotic patients with a standard 20 ml/kg water load. The patients segregated into three classes: class I (n = 6) had normal water load excretion, i.e. greater than 80% excretion over 5 h (mean 82.3 +/- 0.8%); class II (n = 8) had 20-80% excretion (mean 38.6 +/- 4.2%); and class III (n = 7) had less than 20% excretion (mean 12.9 +/- 1.2%). The patients in class III, who had profound impairment of water load excretion, were found to have a higher frequency of tense ascites, lower serum sodium concentrations, diuretic resistance, impairment of urinary sodium excretion, lower inulin and p-aminohippurate clearances, and elevations of plasma arginine vasopressin, aldosterone and norepinephrine concentrations. However, class III could only be distinguished from class II on the basis of excretion of a standard water load. No significant differences were found among the classes in liver function tests. We prospectively followed these patients. Classes I and II patients appear to have a good prognosis, if they avoid ethanol (4 of 5 patients still alive 42-56 months after evaluation). Class III patients have a poor prognosis independent of ethanol intake (all lived less than 5 months, except 1 patients who received a peritoneovenous shunt). Class I patients were found to tolerate continued ethanol consumption better than class II patients. Thus, an early intervention, such as the peritoneovenous shunt, may prolong survival among class III patients; however, this possibility needs to be evaluated in a larger prospective study.

Topics: Adult; Aldosterone; Blood Volume; Diuresis; Female; Humans; Kidney; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Norepinephrine; Renin; Sodium; Vasopressins

The pathogenetic role of ADH in determining hyponatremia in patients with liver cirrhosis is still much debated. Osmotic stimuli are not able to inhibit secretion of ADH in refractory ascites and under such conditions the reduction in effective plasma volume has been put forward as the main cause. Twenty patients with liver cirrhosis and refractory ascites were studied before and during extraction-concentration-reinfusion (ECR) of ascitic fluid by means of Rhodiascit. ADH, renin, aldosterone, blood and urine osmolarity, plasma and urinary concentration of sodium, potassium, chlorine, and the clearance of free water were evaluated. All patients presented high renin values (15.4 +/- 11.7 ng/ml), aldosterone (341 +/- 172 ng/ml), ADH (6.3 +/- 5.2 pg/ml). During ECR, a significant drop was observed in renin (p less than 0.001), aldosterone (p less than 0.001) urinary osmolarity (p less than 0.001) and an equality significant increase in diuresis (p less than 0.001), natriuria (p less than 0.005), kaliuria (p less than 0.001) while ADH presented an irregular course: in 11 cases it remained unchanged, in 3 it fell and in 6 it presented a constant increase. To conclude, data suggest that the diminished filtrate reaching the distal tubule constitutes the greatest cause of the inability to dilute urine in many patients with cirrhosis and that ADH is a permissive rather than a primary factor.

Topics: Aged; Aldosterone; Ascites; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Potassium; Renin; Sodium; Vasopressins

In a series of 602 consecutive sclerotherapies, two cirrhotic patients who had received successful sclerotherapy for control of variceal bleeding while on vasopressin infusions developed mesenteric thrombosis. We found no other cases (in our institution or in literature review) where sclerotherapy or vasopressin infusion alone precipitated mesenteric thrombosis. During vasopressin infusion, there is portal stasis and an increased caudad flow of sclerosant. We suggest that mesenteric thrombosis is a consequence of the combination of these two effects. Direct injection of gastric varices is difficult because of increased postsclerotherapy bleeding, but sclerosis of esophageal varices often leads to their obliteration by the caudad flow of sclerosant. We propose, therefore, that vasopressin infusion during esophageal sclerotherapy may be beneficial in the obliteration of gastric varices. We conclude that (a) in patients without gastric varices, vasopressin infusion increases the incidence of mesenteric thrombosis, and (b) vasopressin infusion during sclerotherapy may enhance the sclerosis of gastric varices.

Topics: Adult; Aged; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Mesenteric Vascular Occlusion; Mesenteric Veins; Portal System; Sclerosing Solutions; Thrombosis; Vasopressins

Topics: Adolescent; Adult; Aged; Erythrocytes; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Potassium; Sodium; Vasopressins; Water-Electrolyte Balance

The pathogenesis of hyponatremia remains debated; therefore, we determined the roles of plasma vasopressin, fluid intake and renal free water excretion in hyponatremic medical patients. We evaluated 100 consecutive hypo-osmolar hyponatremic patients (PNa = 127 +/- 0.7 mM l-1) in a prospective manner. We observed: hyponatremia was often found in association with advanced congestive cardiac failure (twenty-five of 100 patients), liver cirrhosis (16%) and primary volume contraction (29%). There was a 17% in-hospital mortality of hyponatremic patients. This was primarily related to the severity of underlying illnesses rather than to hyponatremia per se. The most consistently observed laboratory finding of hyponatremia was non-osmotic vasopressin stimulation; mean observed PADH was 4.7 +/- 0.7 pg ml-1 and vasopressin was detectable by radioimmunoassay (RIA) in 91% of all patients. In addition to vasopressin stimulation we also found evidence of advanced 'circulatory underfilling' in most hyponatremic patients. Mean urinary osmolality was hypertonic to plasma (441 +/- 17.4 m0sm kg H2O-1). This applied to patients with hyponatremic cardiac failure, liver cirrhosis and volume contraction. Almost all of these patients received high ceiling diuretics. (v) Spontaneous mean daily fluid intake was 2.4 +/- 0.2 l. In summary, our findings suggest that disturbances of vasopressin, fluid intake and renal free water excretion co-operate in the pathogenesis of hyponatremia. In clinical states of advanced circulatory underfilling the occurrence of hyponatremia indicates a poor prognosis of the patient.

Topics: Aged; Drinking; Female; Heart Failure; Humans; Hyponatremia; Kidney Diseases; Liver Cirrhosis; Male; Middle Aged; Vasopressins

In hepatic cirrhosis neurohumoral vasoconstrictor systems are activated to compensate for circulatory disturbances. To study the renin-angiotensin-aldosterone system in more detail, angiotensin converting enzyme in 15 patients with advanced liver disease was inhibited with captopril after moderate sodium restriction. Captopril caused an increase in plasma renin activity (p less than 0.005) and a decrease in plasma aldosterone (p less than 0.025) from an elevated baseline, and a moderate drop in systolic (p less than 0.025) and diastolic (p less than 0.05) blood pressure. Hyperreninaemia after captopril was inversely related to the prevailing plasma sodium level (r = -0.66, p less than 0.01), and the changes in both systolic and diastolic blood pressure were correlated with baseline plasma renin activity (r = 0.49, p less than 0.05 for systolic and r = 0.71, p less than 0.01 for diastolic blood pressure). No change occurred in heart rate or in stimulated plasma noradrenaline and vasopressin levels. The data suggest that in these cirrhotic patients the reactivity of the renin-angiotensin-aldosterone system was still intact, although it occurred at a higher level. They confirm the importance of the renin-angiotensin-aldosterone system in arterial blood pressure regulation in cirrhosis.

Topics: Adult; Aged; Aged, 80 and over; Aldosterone; Blood Pressure; Captopril; Epinephrine; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Norepinephrine; Renin; Vasopressins

Using multiple regression analysis, we have evaluated the clinical and hormonal conditions associated with impaired urinary sodium excretion in normoazotemic patients with cirrhosis and ascites. We retrospectively identified 13 patients with a urinary sodium excretion lower than 15 mmol/day and 13 patients with a sodium excretion higher than 15 mmol/day. Using univariate analysis, all the patients with poor sodium excretion had abnormally high levels of plasma renin activity, plasma aldosterone, and arginine vasopressin. In addition, they had a diastolic blood pressure lower than patients with high urinary sodium excretion, although otherwise were comparable as regards clinical and biochemical data. The consistency of the above associations was then tested by multiple-regression analysis in an attempt to control for potentially confounding factors and to identify only true, independent associations. After a discriminant stepwise procedure, we found that low diastolic blood pressure (P less than 0.01) and high plasma aldosterone levels (P less than 0.05) were the only two conditions independently associated with abnormally low urinary sodium excretion. These findings are consistent with the view that sodium retention in decompensated cirrhosis results from a concomitant severe contraction in the effective blood volume and an increased production and/or retention of aldosterone. The concordance between our results and several pathophysiological findings supports the validity of this statistical approach to confirm physiological and/or clinical predictions.

Topics: Adult; Aged; Aldosterone; Arginine; Ascites; Blood Pressure; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Regression Analysis; Renin; Renin-Angiotensin System; Retrospective Studies; Sodium; Vasopressins; Water-Electrolyte Balance

Topics: Aged; Blood Pressure; Chronic Disease; Female; Hemodynamics; Humans; Liver Circulation; Liver Cirrhosis; Male; Middle Aged; Portal System; Propranolol; Vasopressins

Topics: Ascites; Body Water; Hepatorenal Syndrome; Humans; Hypertension, Portal; Kidney; Liver Circulation; Liver Cirrhosis; Lymph; Sodium; Vasopressins

In 5 patients with cirrhosis and ascites the glomerular filtration rate (GFR), free water clearance (CH2O) and urinary excretion of prostaglandin E2(PGE2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were measured before and after a 3-day treatment with sulindac (400 mg/day). The administration of sulindac induced a marked fall of urinary excretion of PGE2 (from 24.2 +/- 5.5 to 3.8 +/- 1.1 ng/h; p less than 0.05), 6-keto-PGF1 alpha (from 19.9 +/- 2.9 to 5.6 +/- 1.1 ng/h; p less than 0.02) GFR (from 111 +/- 15 to 67 +/- 10 ml/min; p less than 0.01) and CH2O (from 7 +/- 1.5 to 3.7 +/- 1.3 ml/min; p less than 0.02) in all patients studied. The plasma concentration of the active metabolite sulindac sulfide in cirrhotics was 400% of that found in 6 healthy volunteers (9.6 +/- 1.7 vs. 2.4 +/- 0.6 ng/ml). Our results indicate that sulindac, at a dose of 400 mg/day, inhibits the renal synthesis of prostaglandins and impairs renal function in cirrhotics with ascites. These effects are probably related to the marked alteration of sulindac kinetics that occurs in these patients.

Topics: 6-Ketoprostaglandin F1 alpha; Ascites; Body Water; Dinoprostone; Glomerular Filtration Rate; Humans; Indenes; Kidney; Kinetics; Liver Cirrhosis; Norepinephrine; Prostaglandins E; Renin; Sulindac; Vasopressins

In the fasting state the mean portal blood flow demonstrated by the pulsed Doppler system with the Octoson in liver cirrhosis (LC) patients (velocity (PV), 10.2 +/- 3.5 (mean +/- SD) cm/sec, 7.0 +/- 2.6 cm/sec/m2; flow (PF), 579 +/- 262 ml/min, 383 +/- 184 ml/min/m2 (n = 40)) was significantly lower than that in control subjects (PV, 21.2 +/- 5.2 cm/sec, 14.7 +/- 3.9 cm/sec/m2; PF, 966 +/- 344 ml/min, 667 +/- 220 ml/min/m2 (n = 40)). Food intake increased PV by 15% and PF by 15% in LC (n = 8) and increased PV by 56%, PF by 125% in controls (n = 8). Glucagon increased PV by 30% and PF by 52% in LC (n = 10) and increased PV by 50% and PF by 120% in controls (n = 8). Secretin increased PV by 44% and PF by 75% in LC (n = 9) and increased PV by 66% and PF by 142% in controls (n = 8). Vasopressin decreased PV by 42% and PF by 54% in LC (n = 9) and decreased PV by 48% and PF by 62% in controls (n = 8). Insulin, gastrin, and prostaglandin E1 had no effect in either group.

Topics: Adult; Aged; Female; Food; Gastrins; Glucagon; Hormones; Humans; Insulin; Liver Circulation; Liver Cirrhosis; Male; Middle Aged; Prostaglandins E; Secretin; Ultrasonics; Vasopressins

Blood flow in the azygos vein, an index of blood flow through gastro-oesophageal collaterals, was measured by continuous thermal dilution in 100 patients with cirrhosis. Azygos blood flow was directly related to portal pressure (r = 0.54, P less than 0.001). Patients with portal hypertension had very high azygos blood flow (692 +/- 32 ml/min) in comparison with controls (n = 11, 174 +/- 29 ml/min). Patients with previous oesophageal bleeding had similar azygos blood flow as those without, but azygos blood flow was significantly greater in patients with massive or recurrent bleeding than in those with less severe haemorrhage, suggesting that the magnitude of collateral flow may influence the course of variceal bleeding. Patients with grade III varices had higher azygos blood flow than those with grades II or I. In addition, both oesophageal tamponade and vasopressin infusion, procedures of known value in variceal bleeding, markedly reduced azygos blood flow (-40% and -25%, respectively). Measurement of azygos blood flow allows evaluation of haemodynamic changes in the oesophageal collaterals of patients with portal hypertension, and provides useful information on the effect of therapeutic procedures aimed at arresting or preventing variceal haemorrhage.

Topics: Azygos Vein; Blood Flow Velocity; Blood Pressure; Esophageal and Gastric Varices; Esophagoscopy; Female; Gastrointestinal Hemorrhage; Hemodynamics; Humans; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Portacaval Shunt, Surgical; Splenorenal Shunt, Surgical; Vasopressins

Topics: Aldosterone; Blood Proteins; Edema; Edema, Cardiac; Extracellular Space; Glomerular Filtration Rate; Humans; Liver Cirrhosis; Natriuretic Agents; Nephritis; Obesity; Proteins; Vasopressins; Water-Electrolyte Balance

The importance of prostaglandins (PG) in Na and water retention of liver cirrhosis was studied in rats with porta-cava shunt (PCS) compared to control, non-shunted animals. Balance studies were performed in metabolic cages with diets of high, normal and low Na. An experimental phase, during which the animals received either 5 mg X kg-1 of indomethacin daily or placebo, was preceded by a control period and followed by a post-indomethacin period identical to the control phase. In each diet, indomethacin, but non placebo, caused a positive Na balance, correlated with Na intake, which in overall pooled data amounted to -1453 +/- 255 muEq in PCS rats, significantly larger than that measured in controls, of -295 +/- 320 muEq (P less than 0.01). This was attended by a reverse change in K balance of -35.6 +/- 349 muEq versus -1566 +/- 582 muEq (P less than 0.01); glomerular filtration rate (GRF) was unchanged. These data demonstrate that PGs contribute to the control of Na homeostasis in the presence of PCS.

Topics: Animals; Female; Glomerular Filtration Rate; Indomethacin; Liver Cirrhosis; Male; Portacaval Shunt, Surgical; Potassium; Prostaglandins; Rats; Rats, Inbred Strains; Sodium; Vasopressins

Topics: Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Liver Cirrhosis; Vasopressins

Portal cineangiography after umbilicoportal cannulation was used to evaluate esophageal vein perfusion and diameter in 13 cirrhotic patients with severe portal hypertension, prior to and during intravenous vasopressin infusion (0.35 IU per min). Between the 15th and the 20th minute of infusion no change had occurred in the diameters of left gastric veins, esophageal varices, portal veins, or splenic veins. Considerable reduction in the left gastric vein perfusion was indirectly documented by prolongation of washout time (greater than + 145%) and increase in vascular density. These modifications were disproportionate in relation to the simultaneous changes in portal pressure (-16%). These results demonstrate that during vasopressin infusion: (a) there is no constriction of the varices at the level of the lower esophageal sphincter; (b) there is a marked decrease in the perfusion of left gastric vein and esophageal varices; and (c) there is a moderate portal pressure decrease which, by itself, may not be a reliable index of the splanchnic hemodynamic response to vasopressin in cirrhotic patients.

Topics: Adult; Blood Pressure; Cineangiography; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Portal Vein; Stomach; Time Factors; Vasopressins; Veins

We have investigated the effects on systemic, pulmonary, hepatic, and renal hemodynamics, and on blood gases of vasopressin, 0.4 U/min I.V. first alone, then in combination with nitroprusside 1-5 micrograms/kg/min I.V., in 12 patients with liver cirrhosis and portal hypertension. Portal pressures were estimated by the gradient between occluded and free hepatic vein pressures, hepatic blood flow was measured by indocyanine green infusion, renal blood flow by an isotopic method, and cardiac output by thermodilution. Vasopressin alone reduced cardiac output (-23%) and O2 delivery to the tissues (-25%), increased mean arterial pressure (+20%) and filling pressures of the heart (+136%), reduced portal pressures (-36%) (from 19 +/- 1 to 12 +/- 1 mmHg, mean +/- SEM), hepatic blood flow (-35%) (1.33 +/- 0.2 to 0.87 +/- 0.1 l/min), and renal blood flow (-16%) (0.77 +/- 0.07 to 0.65 +/- 0.05 l/min). Adding nitroprusside restored cardiac output, preload and afterload, and renal blood flow to pretreatment values. Oxygen delivery remained depressed (-12%) because of a negative effect on pulmonary gas exchange (physiologic shunt increased from 16 +/- 2 to 28 +/- 4%). Portal pressures remained reduced by 31% and hepatic blood flow by 25%. These results suggest that small doses of I.V. nitroprusside minimize the deleterious hemodynamic effects of vasopressin while maintaining the therapeutic benefit of portal pressure reduction in cirrhotic patients.

Topics: Adult; Coronary Circulation; Drug Therapy, Combination; Female; Ferricyanides; Hemodynamics; Humans; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Male; Middle Aged; Nitroprusside; Pulmonary Circulation; Renal Circulation; Vasopressins

Haemorrhages in the course of cirrhosis and portal hypertension are surgical emergencies. Nevertheless medical treatment may be necessary both to revive the patient and temporarily to check the haemorrhaging itself. Some views are presented on the use of drugs, both those already in clinical use and others at the experimental stage, which appear to be effective in the treatment of haemorrhaging in portal hypertension (Vasopressin, glypressin, prostaglandin, somatostatin, propranolol, cimetidine and ranitidine).

Topics: Cimetidine; Emergencies; Hemorrhage; Humans; Liver Cirrhosis; Lypressin; Propranolol; Prostaglandins; Ranitidine; Somatostatin; Terlipressin; Vasopressins

Topics: Ascites; Body Water; Humans; Hyponatremia; Kidney; Liver Cirrhosis; Peritoneovenous Shunt; Vasopressins

Experimental animal studies have suggested that certain vasodilators could minimize the adverse cardiovascular effects of vasopressin. We investigated the hemodynamic effects of isosorbide dinitrate, alone and in combination with vasopressin, in patients with liver cirrhosis. In 10 patients, isosorbide dinitrate, 5 mg sublingually, reduced portal pressure by 21% as assessed by the gradient between wedged and free hepatic venous pressure, but also decreased mean arterial pressure (MAP) by 20%, pulmonary artery wedge pressure (WP) by 50%, and oxygen delivery (DO2) by 13%. In 6 other patients, isosorbide dinitrate, 5 mg sublingually, combined with vasopressin, 0.4 U/min iv, reduced portal pressure by 37%, increased MAP by 13%, and mean pulmonary artery pressure (MPAP) by 70%, and decreased DO2 by 32%. Thus, isosorbide dinitrate reduces effectively portal hypertension in patients with liver cirrhosis, but also decreases DO2 to the tissues as a consequence of a fall in cardiac output due to decreased preload. At the dosage used in this study, isosorbide dinitrate does not prevent the adverse hemodynamic effects of vasopressin.

Topics: Adult; Aged; Blood Pressure; Cardiac Catheterization; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypertension, Portal; Isosorbide Dinitrate; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Oxygen; Pulmonary Wedge Pressure; Time Factors; Vasopressins

The effects of somatostatin and vasopressin on blood gases, pulmonary and systemic hemodynamics, and portal pressure assessed by the gradient between occluded and free hepatic vein pressures, were investigated in 18 patients with liver cirrhosis. In the first 10 patients, an iv bolus of 250 microgram somatostatin, followed by an infusion of 125 microgram somatostatin over 30 min, caused a sudden rise in pulmonary and systemic vascular pressures lasting 2 to 5 min and accompanied by bradycardia. There was a slight and transient increase in venous admixture (Qsp/Qt) and alveolar-arterial oxygen tension gradients (P(A-a)O2), and a transient reduction in O2 delivery (O2 del) (-11% of the baseline values) and portal pressures (-14%). In the next 8 patients, vasopressin, 0.4 U/min infused over 30 min, caused a more persistent pulmonary and systemic hypertension and bradycardia, a slight increase in P(A.a)O2 and Qsp/Qt, a reduction in O2 del (-27%) and a decrease in portal pressures (-32%). These effects were marked during the entire vasopressin infusion period. Both somatostatin and vasopressin had vasoconstrictive properties and exerted negative effects on hemodynamics and blood gases. Vasopressin appeared to be a more potent drug than somatostatin.

Topics: Adult; Aged; Blood Gas Analysis; Female; Hemodynamics; Humans; Liver Cirrhosis; Male; Middle Aged; Somatostatin; Vasopressins

Topics: Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemodynamics; Humans; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Propranolol; Somatostatin; Vasopressins

Topics: Angioplasty, Balloon; Diagnosis, Differential; Emergencies; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Intubation, Gastrointestinal; Liver Cirrhosis; Portacaval Shunt, Surgical; Prognosis; Sclerosing Solutions; Vasopressins

The effects of 30-minute intravenous and superior mesenteric artery (SMA) infusions of vasopressin in dosages of 2.75 mU and 14 mU per min per kg were compared in five dogs that had cirrhosis and portal hypertension induced by fractionated intraportal polyvinyl alcohol injections. A reduction in portal pressure of approximately 35% was found with both SMA doses and the larger intravenous vasopressin dose, while the smaller intravenous dose reduced portal pressure only 18%. A significantly larger decrease in portal blood flow was found with SMA than intravenous vasopressin administration. Cardiovascular side effects were dose-dependent but independent of the administration mode. Liver enzymes were not affected. Portal vein thrombosis occurred in one dog after the larger SMA dose.

Topics: Animals; Dogs; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hypertension, Portal; Infusions, Intra-Arterial; Infusions, Parenteral; Liver Cirrhosis; Male; Mesenteric Arteries; Vasopressins

The effects of somatostatin on hepatic and systemic hemodynamics were investigated in 17 patients with chronic liver disease and severe portal hypertension during the hemodynamic assessment before elective portal-systemic shunt surgery. The injection of somatostatin (1.0 microgram/kg) caused a decrease of the wedged hepatic venous pressure, from 19.5 +/- SE 1.3 mmHg to 14.0 +/- 1.0 mmHg (p < 0.001). Injections of 0.5 and 2.0 microgram/kg had similar effects. During somatostatin infusion at a constant rate (7.5 microgram/min) there was a reduction of the wedged hepatic venous pressure (-17.0%, p < 0.001) and estimated hepatic blood flow (-17.5%, p < 0.01) but no significant changes in hepatic vascular resistance, cardiac output, systemic blood pressure, peripheral resistance, or cardiopulmonary pressures. In marked contrast to the selective action of somatostatin on splanchnic hemodynamics, vasopressin infusion (0.3 U/min) in 6 patients caused not only significant falls in the wedged hepatic venous pressure and estimated hepatic blood flow (-28.6% and -31.8%, respectively), but also significant changes in the systemic circulation, including a reduction of the cardiac output (-19.7%, p < 0.01) and heart rate (-12.6%, p < 0.01) and an increase of the arterial pressure (+18.8%, p < 0.01) and peripheral resistance (+46.8%, p < 0.01). These results show that somatostatin effectively reduces hepatic blood flow and portal pressure in patients with cirrhosis and severe portal hypertension, without altering the systemic circulation.

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Female; Heart Rate; Hemodynamics; Hepatic Veins; Humans; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Male; Middle Aged; Somatostatin; Vascular Resistance; Vasopressins; Venous Pressure

The effect of somatostatin on splanchnic hemodynamics was determined in 8 patients with cirrhosis of the liver and in 18 normal subjects using arterial-hepatic-venous catheterization. Estimated hepatic blood flow determined by indocyanine green infusion was 1.36 +/- 0.23 L/min (+/- SEM) in patients with cirrhosis and remained unaffected during 30 min of somatostatin (250 microgram/h) administration. Wedged hepatic venous pressure which was elevated to 23 +/- 1.8 mmHg was also uninfluenced. In contrast to somatostatin, an infusion of vasopressin (12 U/h for 30 min) given to the same patients, lowered estimated blood flow by 28% (p < 0.05) and wedged hepatic venous pressure by 18% (p < 0.02). Arterial gastrin and insulin levels were lowered during somatostatin infusion by 33% (p < 0.02) and by 75% (p < 0.005), respectively. In contrast to the cirrhosis, infusion of 250 microgram/h somatostatin into normal subjects was associated with a decrease of estimated hepatic blood flow from 1.20 +/- 0.16 to 0.88 +/- 0.12 L/min (p < 0.01) representing a 27% decline. Arterial gastrin and insulin concentrations were lower (p < 0.01) than in cirrhosis, but the basal levels were lowered by somatostatin to a similar degree in both groups of patients. A higher dose of somatostatin (500 microgram/h) administered to normal subjects resulted in a similar decrease of gastrin and of estimated hepatic blood flow as that seen with 250 microgram/h, whereas a lower dose (125 microgram/h) decreased gastrin but failed to influence estimated hepatic blood flow. Thus, somatostatin at a dose which has been used in the treatment of acute peptic ulcer hemorrhage (250 microgram/h) failed to influence estimated hepatic blood flow and wegded hepatic venous pressure in patients with cirrhosis but lowered splanchnic blood flow in normal subjects. Assuming that this effect contributes to somatostatin's therapeutic efficacy, these results cast doubt on its potential value in the treatment of upper gastrointestinal bleeding of cirrhotics with portal hypertension.

Topics: Dose-Response Relationship, Drug; Gastrins; Humans; Insulin; Liver Circulation; Liver Cirrhosis; Middle Aged; Regional Blood Flow; Somatostatin; Splanchnic Circulation; Vasopressins; Venous Pressure

Topics: Blood Transfusion; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Resuscitation; Shock; Vasopressins

Angiography is of value in the diagnosis and interventional therapy of diffuse hepatocellular disease. Hepatic arteriography is the primary diagnostic method; hepatic venography, portal venography, transvenous liver biopsy and direct cholangiography are complementary. They allow the assessment of type and stage of diseases, their hemodynamic consequences and permit the differentiation of diffuse diseases from tumorous processi. Selective vasopressin infusion and transhepatic catheter obliteration of varices are interventional techniques used to control massive bleeding from gastroesophageal varices--one of the most serious complications of diffuse hepatocellular diseases.

Topics: Acute Disease; Angiography; Budd-Chiari Syndrome; Cholangiography; Chronic Disease; Embolization, Therapeutic; Esophageal and Gastric Varices; Hepatic Veins; Hepatitis; Hepatitis, Alcoholic; Hepatitis, Viral, Human; Humans; Liver Cirrhosis; Phlebography; Portal Vein; Vasopressins

The cirrhotic patient with acute bleeding from esophageal varices has less than a 50% chance of leaving the hospital alive; the outlook for survival is so poor that even desperate measures are worthwhile. Some traditional nonsurgical methods for the control of the bleeding are either ineffective at worst or temporary at best. Balloon tamponade is not recommended at all, but intravenously administered vasopressin may be helpful in allowing the necessary diagnostic investigations to be completed. Most important at this stage are the measures necessary to improve the general status of the patient--restoration of blood volume with fresh blood, prevention of ammonia intoxication, support of the liver, correction of metabolic alkalosis and treatment of the hyperdynamic state with digitalis and cardiotonic drugs. Controlling the bleeding is not the greatest problem--the greatest problem is achieving survival of a critically ill patient who undergoes a formidable operation (e.g., variceal ligation stops the bleeding, but is itself an operation of considerable magnitude). In our hands emergency shunting is the best treatment providing a definitive procedure with the highest 10-year survival rate and the lowest complication rate.

Topics: Emergencies; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostatic Techniques; Humans; Infusions, Intra-Arterial; Infusions, Parenteral; Ligation; Liver Cirrhosis; Mesenteric Arteries; Methods; Portacaval Shunt, Surgical; Vasopressins

Following some remarks on the hyposomolar-hyponatraemic syndrome and on the formation of free water, the possible aetiopathogenetic mechanisms of hyponatraemia in ascitogenous cirrhosis of the liver and in particular the role of ADH are considered. 3 cases out of 18 suffering from ascitic phase cirrhosis in whom inability to produce free water was accompanied by conserved urinary excretion of sodium are reported. One explanation might be the intervention of ADH or of an antidiuretic substance.

Topics: Adult; Aged; Ascites; Female; Humans; Hyponatremia; Liver Cirrhosis; Male; Middle Aged; Osmolar Concentration; Vasopressins; Water-Electrolyte Imbalance

Topics: Blood Volume; Diuretics; Heart Failure; Hospitalization; Humans; Hyperglycemia; Hyponatremia; Kidney Failure, Chronic; Liver Cirrhosis; Stress, Physiological; Surgical Procedures, Operative; Vasopressins

Oesophageal varices are found in the submucosa of the lower oesophageal sphincter (L.E.S.). Portagraphic studies after vasopressin administration showed occlusion of submucosal oesophageal varices and distension of the para-oesophageal veins. Oesophagography and endoscopy after administration of anticholinergics showed considerable dilatation of the submucosal oesophageal varices. Because vasopressin increases, and anticholinergics decrease, L.E.S. pressure it is suggested that L.E.S. pressure is an important factor in the development of submucosal oesophageal varices.

Topics: Blood Pressure; Esophageal and Gastric Varices; Esophagogastric Junction; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Portal Vein; Vasopressins; Vena Cava, Inferior

Morbidity and mortality data from patients with bleeding esophagogastric varices treated with portosystemic shunts relate to the clinical status of the patient and to control of hemorrhage both in the immediate postoperative period as well as later. To obtain comparable data following selective infusion of pitressin into the superior mesenteric artery (SMA), records of 23 consecutive patients with cirrhosis, diagnosed by endoscopy as bleeding from varices and treated with SMA pitressin infusions, were reviewed. Twenty-four infusions were performed and hemorrhage was controlled in 12. Fourteen of the 23 patients subsequently underwent portosystemic shunts. Pitressin infusion controlled hemorrhage preoperatively in seven of these, and five survived one year or longer. The remaining seven, in whom bleeding was not controlled by pitressin, died postoperatively. One of the nine patients not undergoing a portosystemic shunt survived more than eight weeks after pitressin infusion. Vascular complications occurred in seven of 17 who died. These complications and the delay between institution of pitressin and operative therapy to control variceal hemorrhage appears to be a factor in the high mortality rate. Portosystemic shunt remains the best therapy for uncontrolled hemorrhage and to prevent recurrent bleeding from esophageal varices.

Topics: Esophageal and Gastric Varices; Esophagoscopy; Gastrointestinal Hemorrhage; Humans; Infusions, Intra-Arterial; Liver Cirrhosis; Mesenteric Arteries; Portacaval Shunt, Surgical; Vasopressins

The authors report the experience which the have acquired since 1970 in the use of posterior pituitary extract as part of the treatment of gastrointestinal bleeding in cirrhotics. 100 cases have been collected, in 73 patients. These may be divided into two groups: one of 32 patients, who did not receive posterior pituitary extract, with 31 deaths, and one of 41 patients who did receive the extract, with 6 deaths. These figures should be viewed in parallel with the results obtained by other techniques, and it would seem that comparison with other statistics is feasible. In addition, emphasis must be placed upon the simplicity of the administration and surveillance of treatment. Attention is also drawn to the absence of any inherent complication associated with the use of the drug, despite the administration, in certain cases, of high doses.

Topics: Gastrointestinal Hemorrhage; Humans; Injections; Liver Cirrhosis; Oxytocin; Pituitary Gland, Posterior; Tissue Extracts; Vasopressins

Topics: Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hepatic Encephalopathy; Humans; Hypertension, Portal; Liver Cirrhosis; Splenectomy; Splenomegaly; Vasopressins

Topics: Adrenal Gland Diseases; Adrenal Glands; Age Factors; Aged; Brain Edema; Female; Humans; Hyponatremia; Iatrogenic Disease; Kidney; Liver Cirrhosis; Male; Sodium; Vasopressins; Water-Electrolyte Imbalance

Seven patients with compensated liver cirrhosis and esophageal varices, all with a base line wedge hepatic vein pressure greater than 20 cm H2O, received 1-mg doses of vasopressin hormonogen (tGLVP) intravenously. There was a significant mean decrease in wedge pressure of 32%, which lasted for at least 20 min (the duration of measurement), with no change in cardiac output measured. The only cardiac response was a 10 to 20% bradycardia at the height of the moderate pressor response-otherwise the ECG was without change. In 5 patients who received the same tGLVP dose during surgery, direct measurements of portal venous pressure showed the same degree of decrease within 10 min of intravenous injection. Fifteen patients with liver cirrhosis and severe bleeding from esophageal varices were treated conservatively with blood transfusion and tGLVP as the only major drug aside from antibiotics. A nonrandomized control group of 13 patients with the same age distribution, stage of disease, number of previous bleeds, etc., was treated conservatively in the same manner, except that they received either no hemodynamically active drugs or short acting neurohypophysial peptide preparations such as Pitressin. In the control group there was a 61.5% total mortality, a 53.8% mortality directly related to uncontrollable bleeding, and a mean duration of the bleeding episode of 11 days. In the tGLVP-treated group total mortality was 20%, mortality directly related to uncontrollable bleeding was 13.3%, and mean duration of the bleeding episode was 2.9 days. These results appear to justify a large scale clinical trial of the vasopressin hormonogen in this disease.

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Hemodynamics; Humans; Liver Cirrhosis; Lypressin; Male; Middle Aged; Portal Vein; Vasopressins

Topics: Angiography; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Injections, Intra-Arterial; Liver Cirrhosis; Peptic Ulcer Hemorrhage; Stomach Ulcer; Vasopressins

Liver function and clotting tests were evaluated in 39 patients with variceal bleeding prior to superior mesenteric artery vasopressin infusion. In six patients with mild hepatic dysfunction (Child's class A), permanent control of hemorrhage was achieved in all six and all survived the hospitalization. In 21 patients with moderate dysfunction (Child's class B), permanent control of hemorrhage was achieved in 13 (62%) and temporary control for 24 hr or longer in the remaining eight (38%). Survival in class B was 67% (14 of 21). In only four of 12 patients with severe hepatic dysfunction (Child's class C) was control of hemorrhage achieved (33 percent). None of these patients survived. Therapeutic failure also was associated with clotting derangements and the initial bleeding rate. It is concluded that the effectiveness of vasopressin in variceal hemorrhage is a function of the underlying liver disease and derangements in clotting function.

Topics: Adult; Aged; Blood Coagulation; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Injections, Intra-Arterial; Liver Cirrhosis; Male; Mesenteric Arteries; Middle Aged; Vasopressins

One of the may vital functions of the liver is the biodegradation of foreign substances. The enzyme systems responsible for this liver function are frequently the site of drug interactions, both therapeutic and detrimental. Various substances can alter these enzymes by inducing, inhibiting, or competing with them, thus affecting drug response. In most instances, the liver detoxifies and deactivates chemicals, protecting the body from their harmful effects. In some biotransformation processes, however, toxic metabolites are produced that may be injurious to liver tissue as well as other body organs and systems. The effect of alcohol on the liver is a prime example. Although significant strides have been made in recent years, much is yet to be learned concerning the effect of the liver on drugs, the effect of drugs on the liver, and the pharmacologic management of various liver diseases.

Topics: Acetaldehyde; Alcoholism; Chemical and Drug Induced Liver Injury; Diuretics; Drug-Related Side Effects and Adverse Reactions; Ethanol; Hepatic Encephalopathy; Humans; Inactivation, Metabolic; Lactulose; Levodopa; Liver; Liver Cirrhosis; Liver Diseases; Microsomes, Liver; Neomycin; Oxidation-Reduction; Pharmaceutical Preparations; Spironolactone; Vasopressins

Intravenous infusion of vasopressin decreased mesenteric arterial- and portal venous flow in dogs. In 4 of 5 high-risk patients, in whom acu te portosystemic shunting was performed, the peroperative intravenous infusion of vasopressin facilitated the surgical procedure by reducing portal pressure and peroperative bleeding from venous collaterals. In 1 patient with reversed portal flow, the portal pressure and flow were not affected by the vasopressin infusion. No undesirable effects of vasopressin were encountered and all patients survived surgery and the early postoperative period.

Topics: Adult; Aged; Animals; Blood Vessel Prosthesis; Dogs; Female; Humans; Injections, Intravenous; Liver Circulation; Liver Cirrhosis; Male; Middle Aged; Portacaval Shunt, Surgical; Portal Vein; Vasopressins; Venous Pressure

A sensitive and specific double-antibody radioimmunoassay for measuring circulating levels of arginine vasopressin in human serum is described. It is possible to detect arginine vasopressin levels of 1 microU/ml serum without extraction procedure. Normal subjects were found to have 5.7 +/- 4.4 microU/ml after a dehydration period of 12 hours. Water loading diminished arginine vasopressin concentrations while dehydration increased it. Application of furosemide over a period of 14 days brought forth constant but not significant decreases. Subjects suffering from psychogenic polydipsia showed normal levels in spite of drinking 8-12 liters of water per day. Patients suffering from liver cirrhosis with ascites showed significantly higher arginine vasopressin levels, approaching normal values, when ascites was under control.

Topics: Arginine Vasopressin; Diabetes Insipidus; Evaluation Studies as Topic; Furosemide; Humans; Liver Cirrhosis; Lypressin; Osmolar Concentration; Oxytocin; Radioimmunoassay; Thirst; Vasopressins

It has been shown, that measurement of total hepatic blood flow is not of great diagnostic value: normal functioning of this organ is dependant on blood flow only to a minor degree and diseases of the liver usually go along with only minor changes of total blood flow. There are two reasons for this phenomenon: 1) liver cells are able to extract oxygen from blood exhaustively 2) regulation of hepatic arterial blood flow is almost autonomous and compensates well for changes of portal venous blood flow and changes of extrahepatic arterial circulation. Thus normal hepatic arterial blood flow is the most important factor as far as prognosis of shunt operations is concerned. The manifestation of portal-systemic encephalopathy in addition depends not only upon the amount of portal-venous blood bypassing the liver, but also upon arterial blood flow, since urea synthesis is located primarily in zone 1 of liver microcirculation, which is supplied in the first line by the hepatic arterial system. Reduction of portal venous blood flow plays a rather minor role as compared to reduction of arterial flow; it does mean however a considerable loss of important nutritive and trophic factors for the liver.

Topics: Ammonia; Hepatic Artery; Hepatic Encephalopathy; Humans; Liver Circulation; Liver Cirrhosis; Microcirculation; Urea; Vasopressins

In four cirrhotic patients with portal hypertension we have measured some hemodynamic parameters over 60-120 min; portal venous pressure, hepatic venous pressure, mean arterial blood pressure, hepatic blood flow, transsinusoidal vascular resistance and splanchnic oxygen uptake under treatment with Vasopressin (1 IU/min for 10 min) and glypressin (50 mug/kg body weight). The effect on the parameters was less pronounced with glypressin but of longer duration.

Topics: Abdomen; Blood Flow Velocity; Blood Pressure; Humans; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Lypressin; Vascular Resistance; Vasopressins

Topics: Blood Transfusion; Esophageal Diseases; Gastrointestinal Hemorrhage; Humans; Injections, Intra-Arterial; Liver Cirrhosis; Peptic Ulcer Hemorrhage; Recurrence; Stomach Ulcer; Varicose Veins; Vasopressins

Topics: Furosemide; Humans; Hypertension, Portal; Lactulose; Liver Cirrhosis; Spironolactone; Vasopressins

Vasopressin administered as a peripheral infusion (40 U/hr) significantly reduced portal vein pressure in ten awake patients with cirrhosis and portal hypertension. A vasopressin-induced reduction in cardiac output occurred in five of the ten patients (50 per cent). Vasopressin-induced changes in systemic arterial pressure, heart rate, and portal venous pressure were independent of alterations in cardiac output. When the five patients with vasopressin-induced reductions in cardiac output were given a combination of vasopressin and isoproterenol, cardiac output was maintained and the reduction in portal vein pressure was equal to that observed with unopposed vasopressin therapy. Thus, the addition of isoproterenol prevented a vasopressin-induced reduction in cardiac output while permitting vasopressin to reduce portal vein pressure.

Topics: Blood Pressure; Cardiac Output; Drug Evaluation; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Heart Rate; Humans; Infusions, Parenteral; Isoproterenol; Liver Cirrhosis; Male; Portal System; Vasopressins

Renal function studies were done in five children with infantile polycystic disease (IPCD)of kidneys and liver and in four with congenital hepatic fibrosis (CHF). Glomerular filtration rate was reduced in all IPCD patients and in two of four CHF patients. Urinary concentrating ability following water deprivation and vasopressin administration was impaired in all IPCD patients and in three of four CHF patients. During control period, all patients had asymptomatic metabolic acidosis with total carbon dioxide content less than or equal to 20.5 millimols/liter, and net acid excretion (NAE) was reduced in all but one. Ammonium chloride was administered to seven patients; NAE increased in all, but the increments were subnormal in four. The inability to excrete maximally concentrated urine and an adequate amount of net acid may best be explained by abnormal tubular structure or alterations in medullary architecture secondary to progressive scarring, or both.

Topics: Acidosis, Renal Tubular; Adolescent; Ammonium Chloride; Child; Child, Preschool; Cystic Fibrosis; Female; Glomerular Filtration Rate; Humans; Infant; Kidney Concentrating Ability; Kidney Diseases; Kidney Function Tests; Liver Cirrhosis; Male; Vasopressins; Water Deprivation

Selective infusion of vasopressin (0.2 U per min) was performed in 8 cirrhotic patients with portal hypertension who underwent umbilicoportal catheterization. There was a significantly decreased (9.6%) of the free portal venous pressure from 27.0 plus or minus 1.4 mm Hg to 24.4 plus or minus 1.4 mm Hg. In all patients, the portal PO2 significantly decreased with a mean fall of 18.8%. However, in all patients, significant systemic effects were noted: an increase in arterial blood pressure and a decrease in the arterial PO2. In 3 patients, a marked fall of the cardiac output (greater than 2.0 liters per min) was recorded during the selective infusion of vasopressin. It is concluded that if selective infusion of vasopressin into the superior mesenteric artery is efficacious in the control of bleeding varices, the therapeutic effect cannot be totally explained by the lowering of the portal venous pressure in cirrhotic patients with portal hypertension. The risk of vascular thrombosis, the decreased portal PO2, and the systemic effects have to be considered when this approach is used in cirrhotic patients with ruptured esophageal and/or gastric varices.

Topics: Blood Pressure; Cardiac Output; Catheterization; Humans; Hypertension, Portal; Infusions, Parenteral; Liver Cirrhosis; Male; Mesenteric Arteries; Oxygen; Portal System; Portal Vein; Umbilicus; Vasopressins; Venous Pressure

Topics: Adult; Animals; Diuresis; Female; Heart Failure; Humans; Hypertension; Liver Cirrhosis; Male; Rats; Vasopressins; Water-Electrolyte Balance

Topics: Angiography; Contrast Media; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hepatic Artery; Humans; Hypertension, Portal; Injections, Intra-Arterial; Liver Cirrhosis; Mesenteric Arteries; Portacaval Shunt, Surgical; Splenic Artery; Vasopressins

Topics: Alcoholism; Esophageal and Gastric Varices; Hemorrhage; Humans; Hypothermia, Induced; Ligation; Liver Cirrhosis; Pituitary Hormones, Posterior; Portacaval Shunt, Surgical; Pressure; Stomach; Vasopressins

Topics: Animals; Collateral Circulation; Disease Models, Animal; Dogs; Esophageal and Gastric Varices; Hemodynamics; Hypertension, Portal; Liver Circulation; Liver Cirrhosis; Nitrosamines; Portacaval Shunt, Surgical; Preoperative Care; Splenic Artery; Vasopressins; Venous Pressure

Topics: Adult; Aged; Arteriovenous Shunt, Surgical; Catheterization; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Injections, Intra-Articular; Liver Cirrhosis; Male; Mesenteric Arteries; Middle Aged; Perfusion; Vasopressins

Topics: Age Factors; Blood Transfusion; Endoscopy; Esophageal and Gastric Varices; Fiber Optic Technology; Gastrointestinal Hemorrhage; Humans; Intubation, Gastrointestinal; Liver Cirrhosis; Melena; Neurologic Manifestations; Postoperative Complications; Radiography; Retrospective Studies; Vasopressins

Topics: Heart Failure; Humans; Hyponatremia; Liver Cirrhosis; Myxedema; Pituitary Diseases; Radioimmunoassay; Vasopressins

Topics: Aged; Diuresis; Female; Humans; Hyperaldosteronism; Liver Cirrhosis; Male; Middle Aged; Natriuresis; Osmolar Concentration; Sodium; Vasopressins; Water-Electrolyte Balance

Topics: Adrenal Glands; Aldosterone; Ascites; Blood Pressure; Calcium; Creatinine; Cyclic AMP; Edema; Glomerular Filtration Rate; Humans; Hydrocortisone; Hypertension; Kidney; Kidney Failure, Chronic; Kidney Tubules; Liver Cirrhosis; Magnesium; Osmolar Concentration; Phosphates; Potassium; Prostaglandins; Renin; Sodium; Vasopressins; Water-Electrolyte Balance

Topics: Alcoholism; Angiography; Autopsy; Esophageal and Gastric Varices; Fatty Liver; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Infarction; Injections, Intra-Arterial; Intestine, Small; Liver Cirrhosis; Male; Mesenteric Arteries; Mesenteric Vascular Occlusion; Mesenteric Veins; Thrombosis; Vasopressins

Topics: Angiography; Celiac Artery; Duodenal Ulcer; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Injections, Intra-Arterial; Liver Cirrhosis; Mesenteric Arteries; Peptic Ulcer Hemorrhage; Stomach Ulcer; Vasopressins

Topics: Acute Disease; Blood Transfusion; Emergencies; Esophageal and Gastric Varices; Esophagoscopy; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Liver Cirrhosis; Methods; Middle Aged; Vasopressins

The effect of octapressin (2-phenylalanine-8-lysine vasopressin) on renal and intrarenal blood flow was studied in 11 normotensive cirrhotic patients with abnormal renal perfusion. Renal haemodynamic changes were assessed with the (133)Xenon washout technique. Of the six patients given suppressor doses of octapressin intravenously renal blood flow improved in one only. A further three patients responded to the drug in a dose which increased the mean arterial pressure by 5 or more mm Hg. The increase in mean renal blood flow was accompanied by an improvement in renal cortical perfusion. In two patients renal blood flow decreased after the administration of octapressin. These findings, in conjunction with previous reports, suggest that octapressin will only consistently improve renal perfusion in cirrhotic subjects who are hypotensive and in whom the mean arterial blood pressure is raised by the drug, but do not exclude the possibility that octapressin may have a direct renal circulatory effect in some patients.

Topics: Adult; Alkaline Phosphatase; Bilirubin; Blood Flow Velocity; Blood Pressure; Creatinine; Felypressin; Female; Humans; Hypertension, Portal; Hypotension; Kidney; Kidney Failure, Chronic; Liver Cirrhosis; Male; Middle Aged; Serum Albumin; Vasopressins; Xenon

Topics: Hormones, Ectopic; Humans; Hyponatremia; Liver Cirrhosis; Male; Middle Aged; Tuberculosis, Meningeal; Tuberculosis, Pulmonary; Vasopressins

Topics: Adult; Aminohippuric Acids; Creatinine; Diuresis; Humans; Inulin; Kidney Concentrating Ability; Kinetics; Liver Cirrhosis; Male; Mannitol; Middle Aged; Potassium; Sodium; Technetium; Vasopressins; Water

Topics: Adolescent; Adult; Child; Child, Preschool; Esophageal and Gastric Varices; Esophagoscopy; Female; Hemorrhage; Humans; Liver Cirrhosis; Liver Function Tests; Male; Methods; Middle Aged; Portal Vein; Portography; Pressure; Vasopressins

Topics: Adult; Female; Humans; Kidney Concentrating Ability; Kidney Tubules; Liver Cirrhosis; Male; Middle Aged; Osmolar Concentration; Protein Deficiency; Sodium; Urea; Vasopressins; Water

Topics: Blood Protein Disorders; Electrolytes; Humans; Hypertension, Portal; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Serum Albumin; Vasopressins

Topics: Adult; Aged; Alcoholism; Blood Transfusion; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Portacaval Shunt, Surgical; Postoperative Complications; Tampons, Surgical; Therapeutic Irrigation; Time Factors; Vasopressins

Topics: Aminocaproates; Aprotinin; Bilirubin; Blood Proteins; Child; Esophageal and Gastric Varices; Esophagus; Hemorrhage; Humans; Hypertension, Portal; Liver Cirrhosis; Methods; Portacaval Shunt, Surgical; Vasopressins

Topics: Acute Disease; Aldosterone; Angiotensin II; Animals; Anuria; Dogs; Glomerular Filtration Rate; Hypertension, Renal; Kidney; Liver Cirrhosis; Male; Organ Size; Renal Veins; Renin; Sodium; Vasopressins

Topics: Heart Failure; Humans; Liver Cirrhosis; Lung Diseases; Neoplasms; Nephrosis; Vasopressins; Water-Electrolyte Balance

Topics: Edema; Humans; Liver Cirrhosis; Male; Polyuria; Vasopressins

Topics: Acid-Base Equilibrium; Adult; Aged; Blood Pressure Determination; Catheterization; Electrocardiography; Esophageal Neoplasms; Female; Hematocrit; Hodgkin Disease; Humans; Hypertension, Portal; Liver Cirrhosis; Liver Diseases; Lysine; Male; Methods; Middle Aged; Phenylalanine; Portal System; Respiratory Function Tests; Umbilical Veins; Valsalva Maneuver; Vasopressins; Venous Pressure

Topics: Esophageal and Gastric Varices; Felypressin; Female; Fructose; Hemorrhage; Humans; Injections, Intravenous; Liver Cirrhosis; Male; Vasopressins

Topics: Adrenal Cortex Hormones; Alkalosis; Blood Urea Nitrogen; Blood Volume; Diuretics; Edema; Ethacrynic Acid; Furosemide; Glomerular Filtration Rate; Humans; Hyperaldosteronism; Hyperkalemia; Hypokalemia; Hyponatremia; Kidney Failure, Chronic; Kidney Tubules; Liver Cirrhosis; Spironolactone; Triamterene; Vasopressins

Topics: Blood Volume; Catheterization; Dextrans; Esophageal and Gastric Varices; Esophagoscopy; Humans; Liver Cirrhosis; Radiography; Regional Blood Flow; Vasopressins

Topics: Adolescent; Adult; Aged; Alcoholism; Child; Emergencies; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Portacaval Shunt, Surgical; Postoperative Complications; Vasopressins

Topics: Adult; Colon; Humans; Injections, Intravenous; Intestinal Absorption; Liver Cirrhosis; Male; Perfusion; Sodium Chloride; Vasopressins; Water

Topics: Blood Pressure; Humans; Liver Cirrhosis; Portacaval Shunt, Surgical; Portal Vein; Vasopressins

Topics: Adult; Ascites; Diuretics; Ethacrynic Acid; Furosemide; Humans; Liver Cirrhosis; Magnesium; Male; Thiazines; Vasopressins

Topics: Adrenal Insufficiency; Ascites; Brain Injuries; Diabetes Insipidus; Eclampsia; Endocrine System Diseases; Female; Humans; Liver Cirrhosis; Oxytocin; Pregnancy; Vasopressins; Water-Electrolyte Balance

Topics: Diuresis; Humans; Liver Cirrhosis; Lysine; Methods; Phenylalanine; Vasopressins

Topics: Adult; Ascites; Humans; Liver Cirrhosis; Middle Aged; Vasopressins

Topics: Adolescent; Adult; Aged; Animals; Dehydration; Diabetes Insipidus; Diuresis; Diuretics; Edema; Female; Humans; Hypertonic Solutions; Infusions, Parenteral; Liver Cirrhosis; Male; Middle Aged; Plasmacytoma; Rats; Urine; Vasopressins

Topics: Arginine Vasopressin; Drug Therapy; Hepatic Encephalopathy; Humans; Liver Cirrhosis; Neomycin; Vasopressins

Topics: Blood Transfusion; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Hypertension; Hypertension, Portal; Liver Cirrhosis; Mortality; Omentum; Splenectomy; Surgical Procedures, Operative; Vasopressins

Topics: Absorption; Aldosterone; Diuresis; Humans; Infusions, Parenteral; Kidney; Liver Cirrhosis; Mannitol; Methylprednisolone; Vasopressins; Water-Electrolyte Balance

Topics: Alcoholism; Blood Pressure Determination; Blood Volume Determination; Heart Function Tests; Hepatic Veins; Humans; Hypertension; Hypertension, Portal; Iodine Isotopes; Liver Circulation; Liver Cirrhosis; Liver Function Tests; Oxytocin; Pharmacology; Pituitary Hormones, Posterior; Rose Bengal; Serum Albumin; Serum Albumin, Radio-Iodinated; Vasopressins

Topics: Adolescent; Biomedical Research; Blood Pressure; Cardiac Catheterization; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Geriatrics; Humans; Hypertension; Hypertension, Portal; Infusions, Parenteral; Liver Circulation; Liver Cirrhosis; Lysine; Pharmacology; Phenylalanine; Portal Pressure; Portal Vein; Toxicology; Vasopressins

Topics: Addison Disease; Arginine Vasopressin; Avena; Bronchial Neoplasms; Carcinoma, Small Cell; Cushing Syndrome; Gynecomastia; Humans; Hypercalcemia; Hyperthyroidism; Hyponatremia; Hypotension; Liver Cirrhosis; Male; Metabolism; Pathology; Physiology; Small Cell Lung Carcinoma; Sodium; Vasopressins

Topics: Angiotensins; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Humans; Hypertension; Hypertension, Portal; Liver Cirrhosis; Pharmacology; Toxicology; Vasopressins

Topics: Blood Pressure; Blood Pressure Determination; Felypressin; Heart; Hepatic Veins; Humans; Intestines; Liver Circulation; Liver Cirrhosis; Pallor; Pharmacology; Physiology; Splanchnic Circulation; Spleen; Sweating; Toxicology; Vasopressins

Topics: Blood Transfusion; Cryosurgery; Esophageal and Gastric Varices; Gastric Hypothermia; Hematemesis; Hypertension; Hypertension, Portal; Hypothermia, Induced; Liver Cirrhosis; Liver Diseases; Neomycin; Prognosis; Surgical Procedures, Operative; Vasopressins

Topics: Acetylcholine; Animals; Arginine Vasopressin; Blood Pressure; Blood Pressure Determination; Caseins; Cineradiography; Dogs; Epinephrine; Histamine; Liver Circulation; Liver Cirrhosis; Liver Cirrhosis, Experimental; Norepinephrine; Pharmacology; Portal System; Research; Sulfobromophthalein; Vasopressins

Topics: Angiotensins; Arginine Vasopressin; Bilirubin; Blood Circulation; Blood Pressure; Blood Pressure Determination; Heart; Hemoglobinometry; Hepatic Veins; Liver Cirrhosis; Oximetry; Physiology; Serum Albumin; Vasopressins

Topics: Blood Transfusion; Esophageal and Gastric Varices; Esophagoscopy; Humans; Hypertension; Hypertension, Portal; Liver Cirrhosis; Liver Function Tests; Pituitary Hormones, Posterior; Portography; Splenectomy; Surgical Procedures, Operative; Vasopressins; Vitamin K

Topics: Glucocorticoids; Humans; Kidney; Liver Cirrhosis; Mannitol; Metabolism; Methylprednisolone; Pharmacology; Sodium; Vasopressins; Water

Topics: Blood Circulation; Blood Pressure; Felypressin; Heart Function Tests; Hemodynamics; Hepatic Artery; Hepatic Veins; Humans; Hypertension; Hypertension, Portal; Liver Cirrhosis; Pharmacology; Vasopressins

Topics: Albumins; Arginine Vasopressin; Ascites; Blood Chemical Analysis; Humans; Liver Cirrhosis; Spiro Compounds; Urine; Vasopressins

Topics: Emergencies; Esophageal and Gastric Varices; Gastrointestinal Hemorrhage; Hemostasis; Hepatitis; Humans; Liver Cirrhosis; Portacaval Shunt, Surgical; Vasopressins

Topics: Animals; Diuretics; Humans; Liver Cirrhosis; Schistosoma; Schistosomiasis; Vasopressins

Topics: Arginine Vasopressin; Edema; Heart Failure; Humans; Liver Cirrhosis; Vasopressins

Topics: Heart Failure; Humans; Liver Cirrhosis; Vasopressins; Water; Water-Electrolyte Balance

Topics: Blood; Humans; Liver Cirrhosis; Osmolar Concentration; Sodium Chloride; Vasopressins

Topics: Adrenal Cortex; Adrenal Cortex Hormones; Arginine Vasopressin; Humans; Liver Cirrhosis; Vasopressins

Topics: Arginine Vasopressin; Ethanol; Extracellular Fluid; Humans; Liver Cirrhosis; Vasopressins; Water

Topics: Animals; Arginine Vasopressin; Carbon Tetrachloride; Liver Cirrhosis; Liver Cirrhosis, Experimental; Rats; Vasopressins

Topics: Humans; Liver Cirrhosis; Liver Diseases; Vasopressins; Water

Topics: Diuresis; Humans; Liver Cirrhosis; Liver Diseases; Nicotine; Vasopressins

Topics: Adrenal Cortex; Adrenal Cortex Hormones; Humans; Liver Cirrhosis; Pituitary Gland; Pituitary Gland, Posterior; Sodium; Vasopressins

Topics: Edema; Heart Failure; Hormones; Liver Cirrhosis; Pituitary Gland; Pituitary Gland, Posterior; Vasopressins; Water

Topics: Ascites; Electrolytes; Humans; Liver Cirrhosis; Micrococcus; Vasopressins; Water

Topics: Diuresis; Diuretics; Liver Cirrhosis; Pituitary Gland; Vasopressins