Hemodynamic Evaluation of Nonselective \u3b2-Blockers in Patients with Cirrhosis and Refractory Ascites

BACKGROUND:Nonselective \u3b2-blockers (NSBB) have been associated with increased incidence of paracentesis-induced circulatory dysfunction (PICD) and reduced survival in patients with cirrhosis and refractory ascites. AIM:To prospectively evaluate a hemodynamic response to NSBB in cirrhotics listed for liver transplantation with refractory ascites undergoing large volume paracentesis (LVP). METHODS:Patients with cirrhosis and refractory ascites, with an indication to start NSBB in primary prophylaxis for variceal bleeding, were enrolled. During two consecutive LVP, while being, respectively, off and on NSBB, cardiac output (CO), systemic vascular resistances (SVR), peripheral vascular resistances (PVR), and plasma renin activity (PRA) were noninvasively assessed. RESULTS:Seventeen patients were enrolled, and 10 completed the study. Before NSBB introduction, SVR (1896 to 1348\u2009dyn\ub7s\ub7cm-5; p = 0.028) and PVR (47 to 30\u2009mmHg\ub7min\ub7dl\ub7ml-1; p = 0.04) significantly decreased after LVP, while CO showed an increasing trend (3.9 to 4.5\u2009l/m; p = 0.06). After NSBB introduction, LVP was not associated with a significant increase in CO (3.4 to 3.8\u2009l/m; p = 0.13) nor with a significant decrease in SVR (2002 versus 1798\u2009dyn\ub7s\ub7cm-5; p = 0.1). Incidence of PICD was not increased after NSBB introduction. CONCLUSION:The negative inotropic effect of NSBB was counterbalanced by a smaller decrease of vascular resistances after LVP, probably due to splanchnic \u3b22-blockade. This pilot study showed that NSBB introduction may be void of detrimental hemodynamic effects after LVP in cirrhotics with refractory ascites

Usefulness of bioelectrical impedance analysis for monitoring patients with refractory ascites

Background: bioelectrical impedance analysis is a technique for the determination of the hydropic component. The hydropic component, determined by blood volume, could be a reflection of the hemodynamic situation. This study aimed to evaluate the usefulness of peripheral bioelectrical impedance analysis (BIA) for the prediction of hemodynamic changes in large-volume paracentesis and prognosis. Methods: this was a proof-of-concept prospective study of 14 patients with liver cirrhosis and refractory ascites. Peripheral bioimpedance was measured three times using a portable device, IVOL®, before and after large-volume paracentesis, at different frequencies (5, 10, 20, 50, 100 and 200 kHz). Consequently, resistance, reactance and phase angle were obtained, both pre- and post-paracentesis (the difference between them was defined as Δ). Results: the mean age of patients was 62.2 ± 9.6 years, the Child-Pugh was 8.4 ± 1.3 and the MELD score was 15.2 ± 3.9. A direct correlation between the extraction of ascitic fluid and Δresistance (10 kHz [r = 0.722; n = 12; p = 0.008], 20 kHz [r = 0.658; n = 12; p = 0.020] and 50 kHz [r = 0.519; n = 14; p = 0.057]) was observed. The presence of edema was related to lower values of both pre-paracentesis resistance (10 Hz [23.9 ± 8 vs 32.2 ± 4; p = 0.043]) and phase angle (5 kHz [-1.9 ± 2.8 vs 5.9 ± 7.3; p = 0.032]). Pre-paracentesis phase angle was directly correlated with the decline in blood pressure after paracentesis at lower frequencies (5 kHz [r = 0.694; n = 13; p = 0.008] and 10 kHz [r = 0.661; n = 13; p = 0.014]). Lower frequencies of Δphase-angle impacted on patient prognosis (5 kHz [-8.6 ± 5 vs -2.5 ± 2.7; p = 0.021]), patients with Δphase-angle 5 kHz > -4 had a higher rate of mortality (83.3% [5/6] vs 0% [0/6]; logRank 7.306, p = 0.007). Δresistance values were associated with overt HE at six months (10 kHz [4.9 ± 2.5 vs -0.4 ± 4.7; p = 0.046]). Conclusions: in conclusion, a significant correlation between peripheral impedance and hemodynamic changes was found. Impedance was also significantly related to prognosis and overt hepatic encephalopathy

The use of non-selective beta-blockers in patients with cirrhosis: more doubts than certainties

In conclusion, prospective RCT would be needed on the use of NSBBs in decompensated cirrhotic patients with ascites however these trials are difficult to organize and will need a large sample size. A case control study could be useful if the two groups were patients matched for MELD, MELD Na, creatinine, mean arterial pressure, with the same type of ascites (refractory, recurrent, severe) taking or not taking NSBBs. The better and more relevant end pointshould probably be survival. In the meanwhile, the Baveno recommendations can be utilized in clinical practice to remind that severe hypotension is a well-known contraindication for NSBBs which may suggest dose reduction or even therapy discontinuation. Last but not least, NSBBs may have several beneficial effects in patients with cirrhosis beyond the reduction in portal hypertension. They reduce markers of intestinal permeability, bacterial translocation and systemic inflammation, and also the risk of SBP (15,16). The risk to enlarge the indication to stop NSBBs in cirrhotic patients without a real evidence could be as to “throw the baby out with the bath water

TIPS for the treatment of refractory ascites, hepatorenal syndrome and hepatic hydrothorax: a critical update

Refractory ascites is a frequent complication of advanced cirrhosis and is associated with hepatorenal syndrome and hepatic hydrothorax. Large volume paracentesis and pleurodesis are regarded as first-line treatments in patients who do not respond adequately to diuretics. These treatments, however, do not prevent recurrence and carry the risk of worsening of the circulatory dysfunction leading to hepatorenal syndrome. The transjugular intrahepatic portosystemic shunt ( TIPS) has been proposed as an alternative to paracentesis. TIPS reduces the rate of ascites recurrence mainly due to the reduction in the filtration pressure. In addition, TIPS results in a positive effect on renal function, including hepatorenal syndrome, demonstrated by a rapid increase in urinary sodium excretion, urinary volume, and improvement in plasma creatinine concentration. Furthermore, plasma renin activity, aldosterone, and noradrenalin concentrations improve gradually after TIPS insertion suggesting a positive effect on systemic underfilling, the factor of hepatorenal syndrome. As demonstrated recently in two meta-analyses including five randomised studies, TIPS also improves survival when compared with paracentesis. However, the evidence is based on relatively few studies with only 305 patients included. The positive effects of the TIPS are opposed by an increased frequency and severity of episodes of hepatic encephalopathy which may be reduced by both patient selection and reduced shunt diameter. Based on the present knowledge the recommended hierarchy of treatments for refractory ascites may be reconsidered upgrading TIPS in suitable candidates

Usefulness of bioelectrical impedance analysis for monitoring patients with refractory ascites

Background: bioelectrical impedance analysis is a technique for the determination of the hydropic component. The hydropic component, determined by blood volume, could be a reflection of the hemodynamic situation. This study aimed to evaluate the usefulness of peripheral bioelectrical impedance analysis (BIA) for the prediction of hemodynamic changes in large-volume paracentesis and prognosis. Methods: this was a proof-of-concept prospective study of 14 patients with liver cirrhosis and refractory ascites. Peripheral bioimpedance was measured three times using a portable device, IVOL®, before and after large-volume paracentesis, at different frequencies (5, 10, 20, 50, 100 and 200 kHz). Consequently, resistance, reactance and phase angle were obtained, both pre- and post-paracentesis (the difference between them was defined as ¿). Results: the mean age of patients was 62.2 ± 9.6 years, the Child-Pugh was 8.4 ± 1.3 and the MELD score was 15.2 ± 3.9. A direct correlation between the extraction of ascitic fluid and ¿resistance (10 kHz [r = 0.722; n = 12; p = 0.008], 20 kHz [r = 0.658; n = 12; p = 0.020] and 50 kHz [r = 0.519; n = 14; p = 0.057]) was observed. The presence of edema was related to lower values of both pre-paracentesis resistance (10 Hz [23.9 ± 8 vs 32.2 ± 4; p = 0.043]) and phase angle (5 kHz [-1.9 ± 2.8 vs 5.9 ± 7.3; p = 0.032]). Pre-paracentesis phase angle was directly correlated with the decline in blood pressure after paracentesis at lower frequencies (5 kHz [r = 0.694; n = 13; p = 0.008] and 10 kHz [r = 0.661; n = 13; p = 0.014]). Lower frequencies of ¿phase-angle impacted on patient prognosis (5 kHz [-8.6 ± 5 vs -2.5 ± 2.7; p = 0.021]), patients with ¿phase-angle 5 kHz > -4 had a higher rate of mortality (83.3% [5/6] vs 0% [0/6]; logRank 7.306, p = 0.007). ¿resistance values were associated with overt HE at six months (10 kHz [4.9 ± 2.5 vs -0.4 ± 4.7; p = 0.046]). Conclusions: in conclusion, a significant correlation between peripheral impedance and hemodynamic changes was found. Impedance was also significantly related to prognosis and overt hepatic encephalopathy.Peer ReviewedPostprint (published version

Acute-on-chronic liver failure in cirrhosis

The definition of acute-on-chronic liver failure (ACLF) remains contested. In Europe and North America, the term is generally applied according to the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium guidelines, which defines this condition as a syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure and high short-term mortality. One-third of patients who are hospitalized for acute decompensation present with ACLF at admission or develop the syndrome during hospitalization. ACLF frequently occurs in a closed temporal relationship to a precipitating event, such as bacterial infection or acute alcoholic, drug-induced or viral hepatitis. However, no precipitating event can be identified in approximately 40% of patients. The mechanisms of ACLF involve systemic inflammation due to infections, acute liver damage and, in cases without precipitating events, probably intestinal translocation of bacteria or bacterial products. ACLF is graded into three stages (ACLF grades 1–3) on the basis of the number of organ failures, with higher grades associated with increased mortality. Liver and renal failures are the most common organ failures, followed by coagulation, brain, circulatory and respiratory failure. The 28-day mortality rate associated with ACLF is 30%. Depending on the grade, ACLF can be reversed using standard therapy in only 16–51% of patients, leaving a considerable proportion of patients with ACLF that remains steady or progresses. Liver transplantation in selected patients with ACLF grade 2 and ACLF grade 3 increases the 6-month survival from 10% to 80%

Urine Monocyte Chemoattractant Protein-1 Is an Independent Predictive Factor of Hospital Readmission and Survival in Cirrhosis.

MCP-1 (monocyte chemoattractant protein-1) is a proinflammatory cytokine involved in chemotaxis of monocytes. In several diseases, such as acute coronary syndromes and heart failure, elevated MCP-1 levels have been associated with poor outcomes. Little is known about MCP-1 in cirrhosis. AIM: To investigate the relationship between MCP-1 and outcome in decompensated cirrhosis. METHODS: Prospective study of 218 patients discharged from hospital after an admission for complications of cirrhosis. Urine and plasma levels of MCP-1 and other urine proinflammatroy biomarkers: osteopontin(OPN), trefoil-factor3 and liver-fatty-acid-binding protein were measured at admission. Urine non-inflammatory mediators cystatin-C, β2microglobulin and albumin were measured as control biomarkers. The relationship between these biomarkers and the 3-month hospital readmission, complications of cirrhosis, and mortality were assessed. RESULTS: 69 patients(32%) had at least one readmission during the 3-month period of follow-up and 30 patients died(14%). Urine MCP-1 and OPN levels, were associated with 3-month probability of readmission (0.85 (0.27-2.1) and 2003 (705-4586) ug/g creat vs 0.47 (0.2-1.1) and 1188 (512-2958) ug/g creat, in patients with and without readmission, respectively; p<0.05; median (IQR)). Furthermore, urine levels of MCP-1 were significantly associated with mortality (1.01 (1-3.6) vs 0.5 (0.2-1.1) μg/g creat, in dead and alive patients at 3 months; p<0.05). Patients with higher levels of urine MCP-1 (above percentile 75th) had higher probability of development of hepatic encephalopathy, bacterial infections or AKI. Urine MCP-1 was an independent predictive factor of hospital readmission and combined end-point of readmission or dead at 3 months. Plasma levels of MCP-1 did not correlated with outcomes. CONCLUSION: Urine, but not plasma, MCP-1 levels are associated with hospital readmission, development of complications of cirrhosis, and mortality. These results suggest that in cirrhosis there is an inflammatory response that is associated with poor outcomes

Acute-on-Chronic Liver Failure: Definition, Diagnosis, and Clinical Characteristics

Acute-on-chronic liver failure (ACLF) is a recently recognized syndrome in cirrhosis characterized by acute decompensation (AD), organ failure(s), and high short-term mortality. Organ failure(s) is defined by the Chronic Liver Failure-Sequential Organ Failure (CLIF-SOFA) score or by its simplified version Chronic Liver Failure-Organ Failure Assessment (CLIF-OF) score. They include six types of organ failure: liver, renal, coagulation, cerebral, respiratory, and circulatory. One third of patients hospitalized with AD present with ACLF at admission or develop ACLF during hospitalization. Acute-on-chronic liver failure frequently occurs in a closed relationship to a precipitating event. According to the number of organ failures, ACLF is graded into three stages: ACLF-1 = single renal failure or single nonrenal organ failure if associated with renal dysfunction and/or cerebral dysfunction; ACLF-2 = two organ failures; and ACLF-3 = three to six organ failures, with increasing 28-day mortality rate (from 23%–74%). Acute-on-chronic liver failure may develop at any phase during the clinical course of the disease. Patients without prior AD develop a severe form of ACLF

Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.

Sepsis is a systemic inflammatory response to the presence of infection, mediated via the production of many cytokines, including tumour necrosis factor ¿ (TNF-¿), interleukin (IL)-6, and IL-1, which cause changes in the circulation and in the coagulation cascade. There is stagnation of blood flow and poor oxygenation, subclinical coagulopathy with elevated D-dimers, and increased production of superoxide from nitric oxide synthase. All of these changes favour endothelial apoptosis and necrosis as well as increased oxidant stress. Reduced levels of activated protein C, which is normally anti-inflammatory and antiapoptotic, can lead to further tissue injury. Cirrhotic patients are particularly susceptible to bacterial infections because of increased bacterial translocation, possibly related to liver dysfunction and reduced reticuloendothelial function. Sepsis ensues when there is overactivation of pathways involved in the development of the sepsis syndrome, associated with complications such as renal failure, encephalopathy, gastrointestinal bleed, and shock with decreased survival. Thus the treating physician needs to be vigilant in diagnosing and treating bacterial infections in cirrhosis early, in order to prevent the development and downward spiral of the sepsis syndrome. Recent advances in management strategies of infections in cirrhosis have helped to improve the prognosis of these patients. These include the use of prophylactic antibiotics in patients with gastrointestinal bleed to prevent infection and the use of albumin in patients with spontaneous bacterial peritonitis to reduce the incidence of renal impairment. The use of antibiotics has to be judicious, as their indiscriminate use can lead to antibiotic resistance with potentially disastrous consequences