β-Blockers and refractory ascites in cirrhosis: The message of a team of true scientists
Authors: Paolo Angeli
Journal: Journal of Hepatology (2011)

Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: A cross-over studyJournal of HepatologyVol. 55Issue 4PreviewIn patients with cirrhosis and refractory ascites the role of beta-blockers in the development of paracentesis-induced circulatory dysfunction (PICD) is unknown. The aim of this study was to investigate the incidence of PICD before and after discontinuation of beta-blockers in patients with cirrhosis and refractory ascites. A self control cross-over study was performed. Full-Text PDF In 1981, Lebrec et al. proposed for the first time the use of β-blockers in the prophylaxis of variceal bleeding in patients with cirrhosis [1Lebrec D. Nouel O. Corbic M. Benhamou J.P. Propranolol: a medical treatment for portal hypertension.Lancet. 1980; i: 121-124Google Scholar, 2Lebrec D. Poynard T. Hillon P. Benhamou J.P. Propranolol for prevention of gastrointestinal bleeding in patients with cirrhosis. A controlled study.N Engl J Med. 1981; 305: 1371-1374Crossref PubMed Scopus (433) Google Scholar]. This advanced knowledge has been a milestone for research in Hepatology in the last century, and it has inspired an era of lively research about the pathophysiology of the portal system and the potential clinical use of medical treatments able to reduce portal pressure. In particular, several randomized trials and cost-effectiveness analyses have conclusively demonstrated that non selective β-blockers are the first choice medications for primary prophylaxis against variceal bleeding in patients with varices [3De Franchis R. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension.J Hepatol. 2010; 53: 762-768Abstract Full Text Full Text PDF PubMed Scopus (1134) Google Scholar, 4Talwalkar J.A. Kamath P.S. An evidence-based medicine approach to β-blocker therapy in patients with cirrhosis.Am J Med. 2004; 116: 759-766Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. More recently, randomized, controlled trials [5Saab S. DeRosa V. Nieto J. Durazo F. Han S. Roth B. Costs and clinical outcomes of primary prophylaxis of variceal bleeding in patients with hepatic cirrhosis: a decision analytic model.Am. J. Gastroenterol. 2003; 98: 763-770Crossref PubMed Scopus (61) Google Scholar, 6Sarin S.K. Lamba G.S. Kumar M. Misra A. Murthy N.S. Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding.N Engl J Med. 1999; 340: 988-993Crossref PubMed Scopus (329) Google Scholar, 7Jutabha R. Jensen D.M. Martin P. Savides T. Han S.H. Gornbein J. Randomized study comparing banding and propranolol to prevent initial variceal hemorrhage in cirrhotics with high-risk esophageal varices.Gastroenterology. 2005; 128: 870-881Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar] have reported a lower rate of variceal bleeding among patients treated with endoscopic banding – a procedure usually reserved for acutely bleeding varices or secondary prophylaxis – than among patients treated with β-blockers, although no effect on mortality has been noted [3De Franchis R. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension.J Hepatol. 2010; 53: 762-768Abstract Full Text Full Text PDF PubMed Scopus (1134) Google Scholar, 4Talwalkar J.A. Kamath P.S. An evidence-based medicine approach to β-blocker therapy in patients with cirrhosis.Am J Med. 2004; 116: 759-766Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. However, these studies are limited by their short follow-up and small size. Until future studies address these issues, gastroenterologists will continue to choose non selective β-blockers for primary prophylaxis in most patients and reserve endoscopic interventions for primary prophylaxis in patients who cannot tolerate β-blockers, or in those with large varices who live far from medical care facilities [[4]Talwalkar J.A. Kamath P.S. An evidence-based medicine approach to β-blocker therapy in patients with cirrhosis.Am J Med. 2004; 116: 759-766Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. On the other hand, combination therapy with non selective β-blockers and endoscopic banding should be preferred in the prevention of variceal re-bleeding or secondary prophylaxis [[3]De Franchis R. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension.J Hepatol. 2010; 53: 762-768Abstract Full Text Full Text PDF PubMed Scopus (1134) Google Scholar]. The mechanism of action of these medications is complex and varies according to the dose. Low doses of non-selective β-blockers cause unopposed splanchnic vasoconstriction, leading to reduced portal blood flow and, consequently, decreased portal hypertension. As the dose is increased, portal flow is further reduced by the negative effect of these medications on cardiac output. Furthermore, there is also evidence that these medications decrease the development of portosystemic collaterals, an important precursor to the formation of varices [[4]Talwalkar J.A. Kamath P.S. An evidence-based medicine approach to β-blocker therapy in patients with cirrhosis.Am J Med. 2004; 116: 759-766Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. Over the past twenty years, the impairment of the systemic and splanchnic hemodynamics in patients with cirrhosis has been observed as being progressive, so that some hallmarks of this impairment, such as splanchnic arterial vasodilation, the degree of portal pressure and the degree of reduction of the effective circulating volume, and the consequent degree of activation of the systemic endogenous vasoconstrictors systems become more and more evident along the course of liver disease [8Ginès P. Angeli P. Lenz K. Moller S. Moore K. Moreau R. et al.EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.J Hepatol. 2010; 53: 397-417Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar, 9Moreau R. Delegue P. Pessione F. Hillarie S. Durand F. Lebrec D. et al.Clinical characteristics and outcome of patients with cirrhosis and refractory ascites.Liver Int. 2004; 24: 457-464Crossref PubMed Scopus (112) Google Scholar]. More recently, it has also become evident that the secondary progressive increase in cardiac output becomes inadequate to support the progressive fall in peripheral vascular resistance, thereby contributing to a further impairment of the effective circulating volume in the more advanced stages of liver disease [[10]Ruiz-del-Arbol L. Monescillo A. Arocena C. Valer P. Gines P. Moreira V. et al.Circulatory function and hepatorenal syndrome in cirrhosis.Hepatology. 2005; 42: 439-447Crossref PubMed Scopus (473) Google Scholar]. On clinical grounds, these hemodynamic changes result in the definition of distinct clinical stages of liver disease with a markedly different prognosis. In particular, the onset of ascites and its progression toward refractory ascites and/or hepatorenal syndrome has proved to have a deep negative impact on survival [[11]D'Amico G. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.J Hepatol. 2006; 44: 217-231Abstract Full Text Full Text PDF PubMed Scopus (2034) Google Scholar]. Therefore, the questions to be addressed were the following: (a) how does the hemodynamic effect of β-blockers change in the more advanced stages of cirrhosis? And, accordingly, (b) how do β-blockers affect the survival of patients with more advanced cirrhosis, for example in those with refractory ascites, which is defined as a lack of response to high doses of diuretics, or as the recurrent development of side effects when even lower doses of diuretics are used? Prior to the first recent study from the Lebrec's research team [[12]Pagliaro L. Pasta L. D'Amico G. A randomised controlled trial of propranolol for the prevention of initial bleeding in cirrhotic patients with portal hypertension. Preliminary results. The Italian Multicenter Project for Propranolol in the Prevention of Bleeding.Drugs. 1989; 37 ([discussion 74–76]): 48-51Crossref PubMed Scopus (7) Google Scholar], there was no sufficient data to answer these questions. Only a retrospective analysis based on the presence of ascites at randomisation in a multicenter Italian Clinical trial showed that survival was shorter in ascitic patients given propranolol than in those receiving a placebo [[13]Sersté T. Melot C. Francoz C. Durand F. Rautou P.E. Valla D. et al.Deleterious effects of β-blockers on survival in patients with cirrhosis and refractory ascites.Hepatology. 2010; 52: 1017-1022Crossref PubMed Scopus (414) Google Scholar]. Sersté et al. showed that considering patients with cirrhosis and refractory ascites, the median survival was 5.0 months in those treated with propranolol and 20.0 months in patients not treated with propranolol [[12]Pagliaro L. Pasta L. D'Amico G. A randomised controlled trial of propranolol for the prevention of initial bleeding in cirrhotic patients with portal hypertension. Preliminary results. The Italian Multicenter Project for Propranolol in the Prevention of Bleeding.Drugs. 1989; 37 ([discussion 74–76]): 48-51Crossref PubMed Scopus (7) Google Scholar]. As a consequence, the authors suggested for the first time that β-blockers should be contraindicated in patients with cirrhosis and refractory ascites. This conclusion has provoked a strong interest and a lively debate in the scientific community, as highlighted by several letters of comments. Some authors have highlighted limitations on the observational character of the study [14Albillos A. Zamorra J. β-blockers in patients with cirrhosis and refractory ascites.Hepatology. 2010; https://doi.org/10.1002/hep.24032Crossref PubMed Scopus (7) Google Scholar, 15Lo G.H. Effects of β-blockers on survival for patients with cirrhosis and refractory ascites.Hepatology. 2010; ([Epub ahead of print])Google Scholar, 16Wong F. Salerno F. β-blockers in cirrhosis: friend and foe?.Hepatology. 2010; 52: 811-813Crossref PubMed Scopus (41) Google Scholar], on the inclusion criteria, or on the description of the patients included [[14]Albillos A. Zamorra J. β-blockers in patients with cirrhosis and refractory ascites.Hepatology. 2010; https://doi.org/10.1002/hep.24032Crossref PubMed Scopus (7) Google Scholar]. Other authors have objected to what concerns the statistical analysis or the dose of propranolol [[17]Kurt M. Deleterious effects of β-blockers on survival in patients with cirrhosis and refractory ascites.Hepatology. 2010; ([Epub ahead of print])Google Scholar]. Nonetheless, few authors openly discussed the final conclusion of the paper of Sersté et al. even if they recognized that an important question had been raised about the safety of β-blockers in patients with cirrhosis and refractory ascites [[16]Wong F. Salerno F. β-blockers in cirrhosis: friend and foe?.Hepatology. 2010; 52: 811-813Crossref PubMed Scopus (41) Google Scholar]. Based on these results, Lebrec and his research team have now deepened their investigations on the use of β-blockers in patients with cirrhosis and refractory ascites, evaluating the effects of these drugs on the paracentesis-induce circulatory dysfunction (PICD). PICD is a further impairment of systemic and splanchnic hemodynamics and a further decrease in effective arterial blood volume, which is triggered by large volume paracentesis and is detected by an increase in plasma renin activity or concentration (PRC) of at least 50% above baseline one week after paracentesis [[18]Ginès A. Fernández-Esparrach G. Monescillo A. Vila C. Domènech E. Abecasis R. et al.Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.Gastoenterology. 1996; 111: 1002-1010Abstract Full Text PDF PubMed Scopus (487) Google Scholar]. Patients who develop post-paracentesis circulatory dysfunction (PICD) are at risk of developing hyponatremia and renal impairment and have a low probability of survival [[18]Ginès A. Fernández-Esparrach G. Monescillo A. Vila C. Domènech E. Abecasis R. et al.Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.Gastoenterology. 1996; 111: 1002-1010Abstract Full Text PDF PubMed Scopus (487) Google Scholar]. In order to evaluate the effects of β-blockers in the development of PICD, Sersté et al. performed a self control cross-over study [[19]Serst T. Francoz C. Durand F. Rautou P.E. Melot C. Valla D. et al.Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: A cross-over study.J. Hepatol. 2011; 55: 794-799Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar]. Ten patients with cirrhosis and refractory ascites treated with β-blockers were selected. Heart rate, arterial pressure, and plasma renin concentrations (PRC) were collected before, immediately after, and 1 week after large-volume paracentesis associated with intravenous albumin administration. β-blockers were progressively discontinued after complete endoscopic eradication of varices. The clinical and biological evaluation was then repeated. When patients were given β-blockers, the prevalence of PICD was 80%. After the withdrawal of β-blockers, the prevalence of PICD dropped to 10%. Therefore, the authors concluded that the use of β-blockers may be associated with a high risk of PICD in patients with cirrhosis and refractory ascites [[19]Serst T. Francoz C. Durand F. Rautou P.E. Melot C. Valla D. et al.Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: A cross-over study.J. Hepatol. 2011; 55: 794-799Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar]. The results of this study lend further support to the conclusion of the first study of Sersté et al. as the development of a PICD could have contributed to the increased mortality among patients with cirrhosis and refractory ascites who had received propranolol. In addition, they raise some fascinating pathophysiological questions; first of all, can propranolol reduce the cardiac output in patients with cirrhosis and refractory ascites to such an extent to further impair the effective circulating volume? The study of Sersté et al. in the current issue of the Journal of Hepatology has some important limitations. First, it is an exploratory pilot study performed in few patients with cirrhosis and refractory ascites. A randomized controlled trial or a parallel control design in a large sample of patients would probably be more appropriate to evaluate the effects of a specific medication. In addition, the lack of assessment of cardiac dysfunction and the lack of a short follow up to evaluate the clinical consequences of PICD represent other important limitations of the study. Nevertheless, these limitations are clearly indicated in the discussion where the authors stated with great intellectual honesty that "their results should be extrapolated with caution and further studies are needed to confirm these findings". As a consequence, I think that if this manuscript stimulates the design of some randomized controlled clinical trials on the issue of safety of β-blockers in patients with cirrhosis and refractory ascites, the authors will have hit their target. Therefore, my last and most important comment on this study of Sersté et al. will cover its ethical aspects rather than its scientific and methodological ones. I feel that great credit is due to Dr. D. Lebrec and all the other members of his research group for having reviewed, with critical goals, the use of β-blockers in patients with cirrhosis, which, do not forget, represents their most relevant clinical achievement in the last 30 years. This way of conducting scientific research is a rare and precious gift because it is the only way to search for the truth. I want to cite a sentence from the speech of Pope John Paul II at the Pontifical Academy of Sciences, November 13th, 2000 [[20]Pope John Paul II. Speech at the pontifical academy of sciences on November 13th; 2000.Google Scholar]. "Truth, freedom, and responsibility are connected in the scientist. In fact, in embarking upon the path of his research, he understands that he must do it not only with the impartiality required by the objectivity of the method, but also with the intellectual honesty, responsibility, and I would say with a sort of reverence which is suitable to the human spirit in his approach to the truth." I find that in the progressive critical review of their main discovery, Dr. D. Lebrec and his research group reflect the tenor of this definition. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.