Luis Téllez1, Luis Ibáñez-Samaniego2, Candelas Pérez Del Villar3, Raquel Yotti3, Javier Martínez1, Laura Carrión2, Enrique Rodríguez de Santiago1, Maite Rivera4, Ana González-Mansilla3, Óscar Pastor5, Javier Bermejo3, Rafael Bañares2, Agustín Albillos6. 1. Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), CIBEREHD, Universidad de Alcalá, Madrid, Spain. 2. Department of Digestive Diseases, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (iISGM), CIBEREHD, and Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain. 3. Department of Cardiology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (iISGM), CIBERCV, and Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain. 4. Department of Nephrology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Universidad de Alcalá, Madrid, Spain. 5. Servicio de Bioquímica Clínica, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), CIBEROBN, Universidad de Alcalá, Madrid, Spain. 6. Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), CIBEREHD, Universidad de Alcalá, Madrid, Spain. Electronic address: agustin.albillos@uah.es.
Abstract
BACKGROUND & AIMS: The safety of non-selective β-blockers (NSBBs) has been questioned in refractory ascites (RA). We studied the effects of NSBBs on cardiac systolic function, systemic hemodynamics, and renal perfusion pressure (RPP) and function in patients with diuretic-responsive ascites (DRA) and RA. METHODS: We performed a prospective pre-post repeated-measures study in cirrhotic patients, 18 with DRA and 20 with RA on NSBBs for variceal bleeding prophylaxis. Systolic function (by ejection intraventricular pressure difference [EIVPD]), hepatic venous pressure gradient (HVPG), cardiopulmonary pressures, RPP, and sympathetic activation were measured at baseline and after 4 weeks of propranolol. RESULTS: EIVPD was elevated at baseline (RA 4.5 [2.8-5.7] and DRA 4.2 [3.1-5.7] mmHg; normal 2.4-3.6 mmHg) and directly related to the severity of vasodilation and sympathetic activation. NSBBs led to similar reductions in heart rate and HVPG in both groups. NSBBs reduced EIPVD in RA but not in DRA (-20% vs. -2%, p <0.01). In RA, the NSBB-induced reduction in EIPVD correlated with the severity of vasodilation and with higher plasma nitric oxide, norepinephrine and IL-6 (r >0.40, all p <0.05). NSBBs reduced RPP in both groups, but impaired renal function only in patients with RA. Reduced EIPVD correlated with decreases in RPP and estimated glomerular filtration rate (r >0.40, all p <0.01). After NSBB treatment, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) patients with RA, including the 4 fulfilling the criteria for HRS-AKI. CONCLUSION: Renal perfusion and function depend critically on systolic function and sympathetic hyperactivation in RA. NSBBs blunt the sympathetic overdrive, hamper cardiac output, lower RPP below the critical threshold and impair renal function. β-blockade should be used cautiously or even avoided in patients with RA. LAY SUMMARY: We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, β-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function.
BACKGROUND & AIMS: The safety of non-selective β-blockers (NSBBs) has been questioned in refractory ascites (RA). We studied the effects of NSBBs on cardiac systolic function, systemic hemodynamics, and renal perfusion pressure (RPP) and function in patients with diuretic-responsive ascites (DRA) and RA. METHODS: We performed a prospective pre-post repeated-measures study in cirrhotic patients, 18 with DRA and 20 with RA on NSBBs for variceal bleeding prophylaxis. Systolic function (by ejection intraventricular pressure difference [EIVPD]), hepatic venous pressure gradient (HVPG), cardiopulmonary pressures, RPP, and sympathetic activation were measured at baseline and after 4 weeks of propranolol. RESULTS: EIVPD was elevated at baseline (RA 4.5 [2.8-5.7] and DRA 4.2 [3.1-5.7] mmHg; normal 2.4-3.6 mmHg) and directly related to the severity of vasodilation and sympathetic activation. NSBBs led to similar reductions in heart rate and HVPG in both groups. NSBBs reduced EIPVD in RA but not in DRA (-20% vs. -2%, p <0.01). In RA, the NSBB-induced reduction in EIPVD correlated with the severity of vasodilation and with higher plasma nitric oxide, norepinephrine and IL-6 (r >0.40, all p <0.05). NSBBs reduced RPP in both groups, but impaired renal function only in patients with RA. Reduced EIPVD correlated with decreases in RPP and estimated glomerular filtration rate (r >0.40, all p <0.01). After NSBB treatment, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) patients with RA, including the 4 fulfilling the criteria for HRS-AKI. CONCLUSION: Renal perfusion and function depend critically on systolic function and sympathetic hyperactivation in RA. NSBBs blunt the sympathetic overdrive, hamper cardiac output, lower RPP below the critical threshold and impair renal function. β-blockade should be used cautiously or even avoided in patients with RA. LAY SUMMARY: We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, β-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function.
Authors: Nikolaus Pfisterer; Caroline Schmidbauer; Florian Riedl; Andreas Maieron; Vanessa Stadlbauer; Barbara Hennlich; Remy Schwarzer; Andreas Puespoek; Theresa Bucsics; Maria Effenberger; Simona Bota; Michael Gschwantler; Markus Peck-Radosavljevic; Mattias Mandorfer; Christian Madl; Michael Trauner; Thomas Reiberger Journal: Wien Klin Wochenschr Date: 2020-12-03 Impact factor: 1.704
Authors: Ana Garcia Garcia de Paredes; Nicolo Manicardi; Luis Tellez; Luis Ibañez; Felix Royo; Javier Bermejo; Carolina Blanco; Constantino Fondevila; Val Fernandez Lanza; Laura Garcia-Bermejo; Juan Manuel Falcon-Perez; Rafael Bañares; Jordi Gracia-Sancho; Agustin Albillos Journal: Hepatol Commun Date: 2020-12-02
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