Efectos del bloqueo beta-adrenérgico sobre la función cardiaca, la hemodinámica sistémica y hepática y la función renal en los pacientes con cirrosis y ascitis refractoria

Abstract

Introduction: Non-selective beta-blockers (NSBBs), e.g. propranolol, reduce portal pressure and are recommended for prophylaxis of acute variceal bleeding. However, their safety in advanced cirrhosis has been questioned, particularly in patients with refractory ascites (RA). Theoretically, the detrimental effect of betablockers has been related to their negative impact on cardiocirculatory reserve and renal perfusion. However, mechanistic exploratory studies supporting this hypothesis are lacking. Thus, we investigated the effects of NSBBs on cardiac and renal function in patients with cirrhosis and RA and compared them to those observed in cirrhotic patients with diuretic-responsive ascites (DRA). Methods: Multicenter, prospective, observational and controlled study of patients with cirrhosis and ascites in whom NSBBs were indicated for prophylaxis of variceal bleeding. Hepatic venous pressure gradient (HVPG), pulmonary pressures, renal and cardiac function were assessed at baseline, and after 4-weeks on propranolol in both groups. Left ventricular systolic function was evaluated by the ejection intraventricular pressure difference (EIVPD), recently described as the most reliable noninvasive index for this purpose. Results: Median (1st-3rd quartile). Thirty-eigth cirrhotic patients with ascites were included (20 RA,18 DRA). The EIVPD was enhanced at baseline in both groups (RA: 4.3 [2.8-5.7] and DRA: 4.2 [3.1-5.7] mmHg; normal range: 2.4-3.6 mmHg), and was directly related to the severity of peripheral vasodilation, the sympathetic activation and the degree of liver insufficiency (Child-Pugh, r= 0.40, p= 0.01; MELD, r= 0.35, =0.01). NSBBs led to similar reductions in heart rate, cardiac index, and HVPG in both groups. However, NSBBs significantly reduced EIPVD in patients with RA down to 3.1 (2.6-4.1) mmHg (p< 0.01 vs. 4.3 at baseline) but not in DRA (p= 0.33). In patients with RA, NSBBs increased pulmonary artery wedged pressure from 9.9 (7.7-11.3) to 14.1 (11.9-17.7) mmHg (p< 0.01), increased right atrial pressure from 4.4 (3.9-8.9) to 9.6 (6.6-11.0) mmHg (p<0.01), and decreased renal perfusion pressure from 69 (59-80) to 62 (57-71) mmHg (p< 0.01). In these RA patients, the magnitude of reduction in EIPVD (∆EIPVD) directly correlated with the degree of worsening of renal function measured by the changes in cystatin C (r= -0.70, p< 0.01) and creatinine (r= -0.74, p< 0.01). Furthermore, lower baseline values of mean arterial pressure and systemic vascular resistance correlated with the changes in EIPVD and in creatinine induced by NSBBs (r> 0.45, p< 0.05 for all). In addition, changes in EIVPD induced by NSBBs also correlated with higher plasma levels of nitric oxide metabolites, norepinephrine and IL-6 (r> 0.35, p <0.05 for all) in patients with RA. CONCLUSION: NSBBs heavily compromise systolic and renal perfusion at short-term in patients with RA, significant vasodilation (lower mean arterial pressure and systemic vascular resistances), activation and systemic inflammation.