Approximately 60% of patients in the compensated stage of liver cirrhosis develop ascites within 10 years (Ginés et al., 1987) leading to worse outcomes, with mortality rates rising to 50% within 2–5 years of ascites development (Fernández‐Esparrach et al., 2001). Mobilising ascites is key to the treatment and management of the condition, however, approximately 10% of ascitic patients each year develop refractory ascites. The refractory nature of these ascites further worsens survival chances with the probability of 2-year survival dropping to 30% (Ginès et al., 2004; Salerno et al., 2010).
First-line treatment of refractory ascites is often large-volume paracentesis combined with an infusion of albumin (6–8 g/L of ascites removed) (Planas et al., 1990; Sola-Vera et al., 2003). However, large-volume paracentesis hasn’t been shown to reduce mortality. Another alternative treatment is transjugular intrahepatic portosystemic shunt (TIPS), but it has several contradictions and conflicting survival data (D’Amico et al., 2005; Salerno et al., 2007; Bureau et al., 2017).
The use of long-term albumin infusion is one potential solution that has been critiqued and discussed for a number of years. Existing literature has shown mixed results for increasing survival, with some studies showing long-term treatment to be effective in preventing ascites (Gentilini et al., 1999) and others showing that the treatment can reduce ascites recurrence, complications and mortality (Romanelli et al., 2006; Caraceni et al., 2018). In contrast, Solà et al. didn’t find a positive effect on complication development or mortality (Solà et al., 2017), although the dose used by Solà et al. was half of that used by Caraceni et al.
However, the potential benefits of long-term albumin treatment for refractory ascites remain unknown. In this non-randomised, prospective study, 70 patients were recruited and given the option to receive human albumin at a dose of 20 g twice per week in addition to standard of care (SOC) or receive SOC alone (all patients received an infusion of albumin during paracentesis). A total of 45 patients opted for the albumin plus SOC treatment while the remaining 25 patients opted for SOC treatment alone.
Patients were followed until end of the study, liver transplant, or death; mean follow up time was 400.8 ± 256.8 days in the albumin group and 318.7 ± 275.8 days for the SOC group. Despite being a non-randomised study, patients’ baseline characteristics didn’t vary significantly between the two treatment arms.
During the first 24 months of treatment 15 patients died in each treatment arm. A significant difference was seen when comparing the cumulative incidence of 24-month mortality, with the albumin group having a significantly lower mortality rate compared to the SOC group (41.6% vs. 65.5%; p=0.032) (figure 1). The higher cumulative incidence of mortality seen within the SOC group reflects similar results seen in other studies of patients with cirrhosis and refractory ascites, demonstrating the limited positive effects of SOC on survival (Rössle et al., 2000; Gines et al., 2002). Despite the difference, similar causes of death were observed between the two groups, with terminal hepatic failure, hepatocellular carcinoma (HCC), and spontaneous bacterial peritonitis (SBP) being the most common causes.
Multivariate analysis revealed age (subdistribution hazard ratio [sHR] = 1.05; p=0.004), model for end-stage liver disease (MELD) (sHR = 1.08; p=0.017), and long-term albumin treatment (sHR = 0.49; p=0.047) to be independent predictors of mortality.
One of the secondary end-points of this study was the rate of emergency hospitalisations. Given the poor prognosis of liver cirrhosis and the associated complications, hospitalisations are a common occurrence. Long-term treatment with albumin resulted in the albumin group experiencing longer periods free of emergent hospitalisations than those in the SOC group (p=0.008) (figure 2).
Infections and ascites were the most common reasons for hospitalisation in both treatment groups. However, the probability of being hospitalised within 24 months due to hepatic encephalopathy (HE) (26.9% vs. 64.5%; p=0.016), tense ascites (37.1% vs. 71%; p=0.002), SBP (7.9% vs. 50.6%; p=0.004), and non-SBP infections (27.2% vs. 88.6%; p=0.001), were significantly lower in the albumin group compared to the SOC group.
Interestingly, the number of paracentesis and volume of fluid removed wasn’t significantly different between the two treatment groups, although a trend towards fewer paracenteses (1.8 ± 1.2 vs. 2.2 ± 1.3) and reduced volume (12.7 ± 11.1 vs. 15.1 ± 10.3) were seen in the albumin group compared to the SOC group. One hypothesis for the volume removed remaining high in the albumin group, despite reducing emergent hospitalisations, is that the long-term use of albumin limits episodes of rapid ascites development.
A complication which can be of concern is ascites liquid infection. Polymorphonuclear (PMN) leucocytes and culture test of the ascitic fluid were performed on each paracentesis, finding very low incidences of SBP (0.1%), culture-negative neutrocytic ascites (CNNA) (0.4%), and monomicrobial non‐neutrocytic bacterascites (MNNB) (1.1%).
Despite this study being limited due to the single-centre and non-randomised nature, it has demonstrated the potential benefits of long-term albumin on survival and emergent hospitalisations compared to SOC in patients with liver cirrhosis and refractory ascites. Increasing survival is key for patients waiting for liver transplant, as the waiting lists are often long and unpredictable. Could treatment with long-term albumin, therefore be a viable treatment option for patients awaiting liver transplant? To fully answer this question, and the ongoing debate of long-term albumin use, additional larger, multicentre, randomised trials are needed to further assess its efficacy in this patient population.
Catch-up on the debate surrounding hydroxyethyl starch use as we take you on an interactive journey through its changing fortunes. Do you think current restrictions will be enough to change clinical practice?
Bureau C, Thabut D, Oberti F, Dharancy S, Carbonell N, Bouvier A, et al. Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites. Gastroenterology. 2017;152:157–63.
Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al. Long‐term albumin administration in decompensated cirrhosis (ANSWER): an open‐label randomised trial. Lancet. 2018;391:2417–29.
D’Amico G, Luca A, Morabito A, Miragalia R, D’Amico M. Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta‐analysis. Gastroenterology. 2005;129:1282–93.
Di Pascoli M, Fasolato S, Piano S, Bolognesi M, Angeli P. Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites. Liver Int. 2018. [Epub ahead of print].
Fernández‐Esparrach G, Sánchez‐Fueyo A, Ginès P, Uriz J, Quintó L, Ventura PJ, et al. A prognostic model for predicting survival in cirrhosis with ascites. J Hepatol. 2001;34:46–52.
Gentilini P, Casini‐Raggi V, Di Fiore G, Romanelli RG, Buzzelli G, Pinzani M, et al. Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial. J Hepatol. 1999;30:639–45.
Ginès P, Cárdenas A, Arroyo V, Rodés J. Management of cirrhosis and ascites. N Engl J Med. 2004;350:1646–54.
Ginés P, Quintero E, Arroyo V, Terés J, Bruguera M, Rimola A, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology. 1987;7:122–8.
Planas R, Ginès P, Arroyo V, Llach J, Panés J, Vargas V, et al. Dextran-70 versus albumin as plasma expanders in cirrhotic patients with tense ascites treated with total paracentesis. Results of a randomized study. Gastroenterology. 1990;99:1736–44.
Romanelli RG, La Villa G, Barletta G, Vizzutti F, Lanini F, Arena U, et al. Long‐term albumin infusion improves survival in patients with cirrhosis and ascites: an unblinded randomized trial. World J Gastroenterol. 2006;12:1403–7.
Rössle M, Ochs A, Gülberg V, Siegerstetter V, Holl Jm Deibert P, et al. A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med. 2000;342:1701–7.
Salerno F, Cammà C, Enea M, Rössle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta‐analysis of individual patient data. Gastroenterology. 2007;133:825–34.
Salerno F, Guevara M, Bernardi M, Moreau R, Wong F, Angeli P, et al. Refractory ascites: pathogenesis, definition and therapy of a severe complication in patients with cirrhosis. Liver Int. 2010;30:937–47.
Solà E, Solé C, Simón‐Talero M, Martín-Llahí M, Castellote J, Garcia-Martínez R, et al. Midodrine and albumin for prevention of complications of cirrhosis in patients in the waiting list for liver transplantation. A randomized, multicenter, double-blind, placebo-controlled trial. J Hepatol. 2017;66:11.
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This article is a review and summary of the current opinion of albumin in fluid management.
Following the European Medicines Agency’s (EMA) suspension of the marketing authorisations of hydroxyethyl starch (HES) solutions across the European Union (EMA, 2018), Roberts et al., have written an open letter addressed to the World Health Organization (WHO) Director General seeking support for the suspension of HES solutions and expanding it to a worldwide ban.
The Coordination Group for Mutual Recognition and Decentralised Procedures (CMDh) endorse the suspension of hydroxyethyl-starch (HES) solutions, due to serious risks of kidney injury and death in certain patient populations.
This retrospective, observational study used a propensity scoring system to match patients treated with saline with those given a balanced, calcium-free fluid.
Cirrhosis of the liver is a leading cause of mortality. For patients with decompensated cirrhosis, long-term weekly human albumin administration can act as an effective disease-modifying treatment.
Acute kidney injury (AKI) affects one-fifth of major surgery patients, increasing the risk of long-term mortality. This review paper discusses recent study data, discussing the best methods for preventing postoperative AKI.
In 1896 Ernest Starling published his hypothesis for fluid exchange, whereby fluid exchange exists mainly in the capillaries through a process of plasma ultrafiltration across semipermeable membranes (Starling, 1896). But is this 19th century theory something of the past?
Guidelines to promote the early recovery of patients undergoing major surgery recommend a restrictive intravenous-fluid strategy for abdominal surgery. However, the supporting evidence is limited, and there is concern about impaired organ perfusion.
The hypothesis that hypertonic fluid has a dual physiological role, increasing circulatory volume while administering minimal volumes and muting the pro-inflammatory response to injury and illness, may be appealing, but is it superior to isotonic fluids in practice?
A recent PRAC review has recommended suspension of marketing authorisations for HES solutions for infusion across the EU.
The choice of fluid administered during cardiac surgery remains a debated topic, often focussed around colloid solutions containing albumin. Conflicting results from numerous studies have left questions over albumin safety and potential to be superior to crystalloids during surgery. Kingeter et al. hoped to achieve clarity on this controversial topic in a retrospective study of cardiac surgery outcomes over a 12-year period.
Long-term albumin treatment for ascites associated with cirrhosis has been debated in recent years, with mixed results reported for the treatment’s efficacy. In this non-randomised prospective study, Di Pascoli and colleagues question the benefits of long-term albumin in patients with liver cirrhosis and refractory ascites, focussing on survival and emergent hospitalisations. Could this be part of the solution to the ongoing challenge of ascites in cirrhosis?
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