and the CAPPS InvestigatorsLow serum sodium concentration is an independent predictor of mortality in patients with cirrhosis, but its prevalence and clinical significance is unclear. To evaluate prospectively the prevalence of low serum sodium concentration and the association between serum sodium levels and severity of ascites and complications of cirrhosis, prospective data were collected on 997 consecutive patients from 28 centers in Europe, North and South America, and Asia for a period of 28 days. The prevalence of low serum sodium concentration as defined by a serum sodium concentration <135 mmol/L, <130 mmol/L, <125 mmol/L, and <120 mmol/L was 49.4%, 21.6%, 5.7%, and 1.2%, respectively. The prevalence of low serum sodium levels (<135 mmol/L) was high in both inpatients and outpatients (57% and 40%, respectively). The existence of serum sodium <135 mmol/L was associated with severe ascites, as indicated by high prevalence of refractory ascites, large fluid accumulation rate, frequent use of large-volume paracentesis, and impaired renal function, compared with normal serum sodium levels. Moreover, low serum sodium levels were also associated with greater frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome, but not gastrointestinal bleeding. Patients with serum sodium <130 mmol/L had the greatest frequency of these complications, but the frequency was also increased in patients with mild reduction in serum sodium levels (131-135 mmol/L). In conclusion, low serum sodium levels in cirrhosis are associated with severe ascites and high frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome. (HEPATOLOGY 2006;44:1535-1542 I mpairment in body water homeostasis is a common feature of advanced cirrhosis. [1][2][3] This is characterized by a higher rate of renal retention of water in relation to sodium due to a reduction in solute-free water clearance. The consequent inability to adjust the amount of water excreted in the urine to the amount of water ingested leads to dilutional hyponatremia. In recent years, great advances have been made in the knowledge of the pathogenesis of reduced solute-free water clearance in patients with advanced cirrhosis. The inability to excrete an adequate amount of solute-free water in the urine is related to several factors, the most important of which is increased vasopressin release. A reduction of effective circulating volume due to arterial splanchnic vasodilation is considered the afferent factor leading to a baroreceptormediated nonosmotic stimulation of vasopressin release in cirrhosis. 4 Additional factors in the pathogenesis of hyponatremia in cirrhosis are thought to be reduced production of solute-free water due to a reduced sodium delivery to the distal tubule as a consequence of reduction of glomerular filtration rate and/or increase of sodium reabsorption in the proximal tubule. [4][5][6][7] Several studies in large cohorts of patients with cirrhosis have shown that the renal ability to...

PPIs were used by 52% of this international cirrhosis cohort during a 1-year period and was a risk factor for developing HE and SBP. These findings are consistent with the hypothesis that PPIs may increase translocation of gut bacteria. (Hepatology 2016;64:1265-1272).

for the HypoCAT study investigators* Hyponatremia in cirrhosis is associated with significant morbidity and mortality and complicates ascites management. Vasopressin receptor antagonists improve serum sodium concentration by increasing renal solute-free water excretion, but their effects on the management of ascites have not been assessed. Our aim was to investigate the effects of satavaptan, a highly selective vasopressin V 2 receptor antagonist, on ascites management and serum sodium in hyponatremic patients with cirrhosis. A total of 110 patients with cirrhosis, ascites, and hyponatremia (serum sodium <130 mmol/L) were included in a multicenter, double-blind, randomized, controlled study comparing three fixed doses of satavaptan (5 T he development of ascites in cirrhosis is the result of an abnormal regulation of the extracellular fluid volume that causes a positive fluid balance due to a persistently increased renal sodium and water reabsorption. Several lines of evidence indicate that this renal dysfunction is related to impairment in circulatory function characterized by splanchnic arterial vasodilation, secondary to sinusoidal portal hypertension. This causes a reduction in the effective arterial blood volume and a subsequent homeostatic activation of vasoconstrictor and sodium-retaining and water-retaining systems, including the renin-angiotensin-aldosterone system, the sympathetic nervous system, and vasopressin, which are responsible for sodium and water retention. 1,2 According to this pathogenesis, the pharmacological approach to treatment of ascites has been based on the administration of spironolactone, a drug that antagonizes the effect of aldosterone, which reduces the increased extracellular fluid volume by increasing renal sodium and water excretion. 3 However, a significant proportion of patients with ascites either do not respond to spironolactone or require the administration of high doses of the drug, which increases the risk of From the

Objective Satavaptan, a vasopressin V2 receptor antagonist, has been shown to improve the control of ascites in cirrhosis in short-term phase II studies. The aim of this study was to evaluate the efficacy and safety of satavaptan in three different populations of patients with cirrhosis and ascites. Methods 1200 patients were included in three randomised double-blind studies comparing satavaptan with placebo in uncomplicated ascites (study 1: n¼463 patients) and difficult-to-treat ascites, with and without concomitant diuretic treatment (studies 2 and 3: n¼497 and n¼240 patients, respectively). Results Satavaptan was not more effective than placebo in the control of ascites in any of the populations studied as estimated by the primary efficacy endpoints: worsening of ascites (study 1) and the cumulative number of largevolume paracenteses during 12 weeks (studies 2 and 3). Nevertheless, some of the secondary efficacy endpoints related to the treatment of ascites were met in the three studies, suggesting a slight advantage of satavaptan over placebo in delaying ascites formation. Moreover, satavaptan was more effective than placebo in improving the serum sodium concentration in patients with hyponatraemia.

The safety of nonselective b-blockers (NSBBs) in advanced cirrhosis has been questioned. We used data from three satavaptan trials to examine whether NSBBs increase mortality in cirrhosis patients with ascites. The trials were conducted in 2006-2008 and included 1198 cirrhosis patients with ascites followed for 1 year. We used Cox regression to compare allcause mortality and cirrhosis-related mortality between patients who did and those who did not use NSBBs at randomization, controlling for age, gender, Model for End-Stage Liver Disease score, Child-Pugh score, serum sodium, previous variceal bleeding, cirrhosis etiology, and ascites severity. Moreover, we identified clinical events predicting that a patient would stop NSBB treatment. At randomization, the 559 NSBB users were more likely than the 629 nonusers to have a history of variceal bleeding but less likely to have Child-Pugh class C cirrhosis, hyponatremia, or refractory ascites. The 52-week cumulative all-cause mortality was similar in the NSBB user and nonuser groups (23.2% versus 25.3%, adjusted hazard ratio 5 0.92, 95% confidence interval 0.72-1.18), and NSBBs also did not increase mortality in the subgroup of patients with refractory ascites (588 patients, adjusted hazard ratio 5 1.02, 95% confidence interval 0.74-1.40) or in any other subgroup. Similarly, NSBBs did not increase cirrhosis-related mortality (adjusted hazard ratio 5 1.00, 95% confidence interval 0.76-1.31). During follow-up, 29% of initial NSBB users stopped taking NSBBs, and the decision to stop NSBB treatment marked a sharp rise in mortality and coincided with hospitalization, variceal bleeding, bacterial infection, and/or development of hepatorenal syndrome. Conclusion: This large and detailed data set on worldwide nonprotocol use of NSBBs in cirrhosis patients with ascites shows that NSBBs did not increase mortality; the decision to stop NSBB treatment in relation to stressful events may have added to the safety. (HEPATOLOGY 2016;63:1968-1976 SEE EDITORIAL ON PAGE 1771U se of nonselective b-blockers (NSBBs) as secondary prevention of variceal bleeding was introduced in 1981. (1) Since then, numerous randomized trials and meta-analyses have documented NSBBs' efficacy in preventing variceal bleeding, (2,3) and today NSBBs are the standard pharmacological treatment for primary and secondary prevention of variceal bleeding. (4,5) They reduce portal pressure by decreasing cardiac output (b 1 -blockade) and splanchnic blood flow (b 2 -blockade). (6) Surprisingly, in 2010 serious concerns about the safety of NSBB use in cirrhosis patients with refractory ascites were raised by a single-center observational Abbreviations: CI, confidence interval; HR, hazard ratio; HRS, hepatorenal syndrome; MAP, mean arterial pressure; MELD, Model for End-Stage Liver Disease; NSBB, nonselective b-blocker; SBP, spontaneous bacterial peritonitis.