Beta-blockers in patients with refractory ascites: To treat or not to treat. That is the question? But, what is the answer?†
Potential conflict of interest: Nothing to report.
Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study. J Hepatol , , , , , , et al 2011;55:794–;799
Mónica Guevara M.D., Ph.D.*, * Liver Unit Hospital Clinic. Barcelona, Institut d'Investigacions, Biomediques August-Pi-Sunyer, Ciberehd.
Sersté T, Francoz C, Durand F, Rautou PE, 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;55:794-799. (Reprinted with permission.)
Background & Aims: In 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. Methods: Patients with cirrhosis and refractory ascites treated with beta-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. Beta-blocker therapy was progressively discontinued after complete endoscopic eradication of varices. The clinical and biological evaluation was then repeated. The presence of PICD was defined as an increase in PRC of at least 50% above baseline 1 week after paracentesis. Results: Ten patients were included (nine men, mean age 59.1 ± 10.7 years old). The MELD score was 17.7 ± 4.4 and eight patients were Child–Pugh C. When patients were given betablockers,the heart rate did not change immediately after paracentesis while mean arterial pressure significantly decreased; PICD developed in eight patients. After beta-blockers were discontinued, the heart rate significantly increased immediately after paracentesis and mean arterial pressure significantly decreased; PICD only developed in one patient; the difference in the incidence of PICD was significant when these same patients were treated with beta-blockers. Conclusions: The use of beta-blockers may be associated with a high risk of PICD in patients with cirrhosis and refractory ascites.
Treatment with beta-blockers is the treatment of choice for primary prophylaxis of variceal bleeding in cirrhotic patients. It has been used for over three decades because of its effectiveness in preventing primary variceal bleeding.1, 2 In addition, meta-analysis of existing studies showed a trend toward improved survival in treatment with beta-blockers.3, 4 Therefore, based on the evidence published during all these years in several studies, treatment with beta-blockers has become the recommended treatment to prevent primary variceal bleeding in patients with cirrhosis.5, 6 Also, in the last conference of Baveno V Consensus Workshop, treatment with beta-blockers was strongly recommended not only in patients with medium or large varices, but also in patients with red veins with small wale marks or Child-Pugh class C.7 In 2010, Sersté et al. published a study evaluating the effect of beta-blockers on survival in patients with refractory ascites.8 The result of that study showed that administration of beta-blockers to patients with refractory ascites was associated with poorer survival, in comparison to patients treated without beta-blockers. However, the design of that study had major methodological problems. The two groups of patients compared in the study had baseline clinical and analytical differences. The group of patients treated with beta-blockers had esophageal varices, and therefore they showed indication for receiving the treatment. In contrast, in the untreated group, the majority of patients had no varices (only 4 of 74 had varices). In addition, the treated group had a significantly higher bilirubin level with a more severe liver failure (estimated by a greater Child-Pugh classification). Based on the lower survival observed in this study in the group of patients treated with beta-blockers and, to evaluate whether this treatment could impair the already altered circulatory function in patients with cirrhosis and ascites, the same group of investigators designed the following study. In the current study, Sersté et al. evaluated the effect of beta-blockers on postparacentesis circulatory changes in patients with refractory ascites.9 In this study, the investigators evaluated the effect of paracentesis on circulatory function estimated by the increase in plasma renin concentration measured on day 6 after paracentesis. The study was designed as a crossover study including 10 patients with refractory ascites. The first study evaluated the patients while taking beta-blockers. Determinations of heart rate, blood pressure, and renin concentration were performed at baseline immediately after and on day 6 after paracentesis. Later, the same group of patients were treated with endoscopic band ligation to eradicate varices. When varices were eradicated, patients started with a progressive decrease of beta-blockers until withdrawal of treatment. After, when the patients were without treatment, paracentesis was repeated and the same determinations as in the first study were performed. The investigators showed that patients studied while taking beta-blockers developed postparacentesis circulatory dysfunction (PPCD) in 9 of the 10 patients studied (90%). PPCD was defined as the increase in plasma renin concentration over 50% of baseline measured on day 6 after paracentesis.10 Patients studied during treatment with beta-blockers presented a lack of increase in heart rate and blood arterial pressure. These effects are not unexpected, because aim of beta-blockers is to decrease heart rate and blood pressure, and the adequate dose of treatment is to administrate the lower dose in which the heart rate is maintained at approximately 55-60 beats/minute without increasing after exercise. After stopping treatment with beta-blockers and before the inclusion in the second study, patients showed values of renin concentration similar to those at baseline in the first study. However, in this case after paracentesis, an increase in heart rate and blood pressure was observed. With these results, the investigators suggest that beta-blockers may be harmful in patients with refractory ascites, justifying their conclusion on the development of PPCD. PPCD is an effect that is associated with an increased rate of kidney failure and increased long-term mortality. In addition, the PPCD associated with increased mortality is a silent, “irreversible” event.10 This was not the case in the patients studied by Sersté et al., because all of them showed a decrease in renin concentration after beta-blocker withdrawal. Therefore, one possibility to explain the high incidence of PPCD in the group of patients treated with beta-blockers may be to consider the increase in plasma renin concentration as a compensatory mechanism, because they cannot raise their heart rate and neither can they increase their cardiac output to maintain blood arterial pressure.
The hemodynamic changes that occur after large-volume paracentesis has been widely investigated in several studies.11, 12 It is well known that within the first 12 hours after paracentesis there is an improvement in circulatory function with increase in cardiac output and stroke volume, a reduction in cardiopulmonary pressure, and deactivation of vasoconstrictor systems. However, this early phase is followed by opposite hemodynamic changes with reduction in cardiac output and marked activation of vasoconstrictor systems.11 The cause of PPCD is related to an accentuation of arteriolar vasodilatation, already present in this group of patients.13 The impairment in vasodilation is probably related to multifactorial factors, including an increased synthesis of vasodilator substances in the splanchnic vascular territory and mechanical changes secondary to mechanical decompression. These effects occur in 80% of patients treated with paracentesis without plasma expansion after the procedure that decreases to 20% in patients treated with albumin after paracentesis. The aim of giving albumin is to maintain the initial beneficial effects produced immediately after paracentesis. One point that deserves to be mentioned is that most of the studies evaluating hemodynamic changes postparacentesis to evaluate PPCD excluded patients who were treated with beta-blockers. So, we do not know the meaning of PPCD in this group of patients. Beta-blockers would prevent the immediate increase in cardiac output after paracentesis, and therefore the increase in renin concentration may be the expression of the only homeostatic response to maintain arterial pressure. A chronotropic dysfunction has been described in patients with cirrhosis and advanced liver failure. It may be likely related to a down-regulation of beta-receptors. Therefore, it may be possible that treatment with beta-blockers may prevent proper cardiocirculatory response to certain events, such as infection or sepsis, and perhaps in these patients, treatment with beta-blockers may be detrimental.
Finally, it has also been reported that beta-blockers decrease cardiac index (CI), and in patients with ascites and low CI, they may potentially worsen hemodynamics and band ligation may therefore be the preferred treatment as prophylaxis against variceal bleeding.14
Therefore, the ideal study to define the effect of beta-blockers on hemodynamic function and survival in patients with refractory ascites should be a randomized, long-term control trial comparing two groups of patients with the same clinical and analytical characteristics in which one group of patients receive beta-blockers and the other was treated with endoscopic band ligation. In conclusion, the debate is open and further studies are required before changing the current clinical guidelines.7