Betablockers induce cardiac chronotropic incompetence
Authors: Aleksander Krag, Søren Møller, Andrew K. Burroughs, Flemming Bendtsen
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 We read with great interest the paper by Sersté et al. regarding effects of non-selective beta-blockers (BB) and paracentesis induced circulatory dysfunction (PICD) [[1]Serste 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 (154) Google Scholar]. This is the first study to explore the background for potential deleterious effects of BB in refractory ascites, as suggested in a previous study by the authors [[2]Serste T. Melot C. Francoz C. Durand F. Rautou P.E. Valla D. et al.Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.Hepatology. 2010; 52: 1017-1022Crossref PubMed Scopus (432) Google Scholar]. The high risk of PICD after BB treatment seems related to an inability to increase heart rate during a circulatory challenge. BB bind to β1 and β2-adrenoreceptors and thereby compete with the binding of norepinephrine (NE) and epinephrine. Blocking the β1 receptors reduces the heart rate as well as inotropy and hence the cardiac output even in decompensated patients [[3]Bendtsen F. Henriksen J.H. Sorensen T.I. Propranolol and haemodynamic response in cirrhosis.J Hepatol. 1991; 13: 144-148Abstract Full Text PDF PubMed Scopus (41) Google Scholar]. A low dose of selective BB in congestive heart failure has been shown to have a cardioprotective effect possibly related to a diminished beta-adrenergic drive on the diseased heart. This may also be the case in cirrhosis. However, in cirrhosis BB are generally titrated to maximum tolerable doses to reduce risk of variceal bleeding. In this study, the mean dose was 132 mg/day and 7 out of 10 patients received 160 mg/day. This level is higher, especially in the decompensated, than the doses in most randomised trials with BB in the prevention of variceal bleeding [2Serste T. Melot C. Francoz C. Durand F. Rautou P.E. Valla D. et al.Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites.Hepatology. 2010; 52: 1017-1022Crossref PubMed Scopus (432) Google Scholar, 4Gluud L.L. Langholz E. Krag A. Meta-analysis: isosorbide-mononitrate alone or with either beta-blockers or endoscopic therapy for the management of oesophageal varices.Aliment Pharmacol Ther. 2010; 32: 859-871Crossref PubMed Scopus (56) Google Scholar]. In the study by Sersté et al. 80% of the patients who received BB developed PICD, which is more frequent than previously reported [5Gines A. Fernandez-Esparrach G. Monescillo A. Vila C. Domenech E. Abecasis R. et al.Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.Gastroenterology. 1996; 111: 1002-1010Abstract Full Text PDF PubMed Scopus (497) Google Scholar, 6Sola-Vera J. Minana J. Ricart E. Planella M. Gonzalez B. Torras X. et al.Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory dysfunction in cirrhotic patients with ascites.Hepatology. 2003; 37: 1147-1153Crossref PubMed Scopus (182) Google Scholar]. Whether this is related to the high BB doses used is unclear [[7]Senzolo M. Nadal E. Cholongitas E. Burroughs A.K. Is hydrophobia necessary for the hepatologist prescribing nonselective beta-blockers in cirrhosis?.Hepatology. 2011; 53: 2149-2150Crossref PubMed Scopus (16) Google Scholar], but nevertheless, intensive betablockade and resultant decreased heart rate and cardiac output must have been present. There is evidence that a chronotropic incompetence partly based on down-regulation and desensitisation of beta-receptors is involved in the cardiac dysfunction in cirrhosis especially in the most advanced stages [[8]Møller S. Henriksen J.H. Cirrhotic cardiomyopathy.J Hepatol. 2010; 53: 179-190Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar]. A further pharmacological blockade of cardiac beta-receptors may further compromise the cardiac function. The result is an augmented cardiac counter-regulatory response to a sudden vasodilatation-induced decrease in arterial blood pressure. In decompensated cirrhosis, the circulation and perfusion of vital organs are dependent on a sufficient cardiac reserve. The normal circulatory response to a number of stressful events such as for example PICD, infections, and haemorrhage is an increase in cardiac output based on the ability to increase heart rate and contractility to meet the increased demand of perfusion. Thus, regulation of heart rate is the main physiological mechanism to compensate for circulatory stress in patients partly refractory to endogenous vasoconstrictors. The exact mechanisms behind PICD is not fully understood, but two circulatory challenges may be present namely the decreases in systemic vascular resistance and central blood volume with decreased venous return and therefore impaired cardiac filling and a reduced cardiac output. Thus, during PICD there is a further vasodilation, which is partly resistant to the physiological counter-regulatory vasoconstriction by the renin–angiotensin–aldosterone and sympathetic nervous systems [[9]Ruiz-del-Arbol L. Monescillo A. Jimenez W. Garcia-Plaza A. Arroyo V. Rodes J. Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis.Gastroenterology. 1997; 113: 579-586Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar]. An increase in organ perfusion in advanced cirrhosis can only be accomplished by a heart rate mediated increase in cardiac output. If BB abolish the cardiac compensatory reserve during such circulatory challenges the cirrhotic circulation becomes extremely vulnerable. We believe that the study strongly suggests that an impaired cardiac function at the stage of refractory ascites is important. However, data on the consequences for survival with BB need to be confirmed [[7]Senzolo M. Nadal E. Cholongitas E. Burroughs A.K. Is hydrophobia necessary for the hepatologist prescribing nonselective beta-blockers in cirrhosis?.Hepatology. 2011; 53: 2149-2150Crossref PubMed Scopus (16) Google Scholar]. Very high doses of BB, need to be used with great care, or perhaps avoided in patients with refractory ascites. Banding ligation can be substituted for BB, for the prevention of variceal bleeding if BB are not being given. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.