Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis

Abstract

Extracorporeal albumin dialysis (ECAD) may improve severe hepatic encephalopathy (HE) in patients with advanced cirrhosis via the removal of protein or non-protein-bound toxins. A prospective, randomized, controlled, multicenter trial of the efficacy, safety, and tolerability of ECAD using molecular adsorbent recirculating system (MARS) was conducted in such patients. Patients were randomized to ECAD and standard medical therapy (SMT) or SMT alone. ECAD was provided daily for 6 hours for 5 days or until the patient had a 2-grade improvement in HE. HE grades (West Haven criteria) were evaluated every 12 hours using a scoring algorithm. The primary endpoint was the difference in improvement proportion of HE between the 2 groups. A total of 70 subjects [median age, 53; 56% male; 56% HE grade 3; 44% HE grade 4; median model for end-stage liver disease (MELD) 32 (11-50) and CPT 13 (10-15)] were enrolled in 8 tertiary centers. Patients were randomized to ECAD ؉ SMT (n ‫؍‬ 39) or SMT alone (n ‫؍‬ 31). Groups were matched in demographics and clinical variables. The improvement proportion of HE was higher in ECAD (mean, 34%; median, 30%) versus the SMT group (mean, 18.9%; median, 0%) (P ‫؍‬ 0.044) and was reached faster and more frequently than in the SMT group (P ‫؍‬ 0.045). H epatic encephalopathy (HE) is a complex neuropsychiatric syndrome commonly seen in patients with advanced liver disease. HE arises from the effects of circulating toxins on cerebral functions. Putative toxic molecules accumulate in patients with liver decompensation because of increased production, portal-systemic shunting, or lack of hepatic detoxification. 1 Patients with advanced cirrhosis and a superimposed acute liver injury often decompensate and present with manifestations of hepatic failure, including worsening HE and coma. 2 .Current therapy for HE includes the use of nonabsorbable disaccharides or poorly absorbable antibiotics, as proposed more than 3 decades ago. 3 However, standard therapy is less effective in patients with severe degrees of liver failure. 4,5 Under these circumstances, the concept of supporting the failing liver for a time while correcting the precipitating event might help patients recover from HE or be stabilized until they receive a liver transplant. 6 Extracorporeal albumin dialysis (ECAD) using the molecular adsorbent recirculating system (MARS) is a new method of hemodiafiltration whereby blood is dialyzed against an albumin-containing solution across a high-flux membrane. 7 The technique allows combined removal of albumin-bound and water-soluble toxins. [8][9][10][11][12] In uncontrolled trials of ECAD using the MARS device, patients had a reduction in ammonia levels, clear-

Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality†‡§

“…4,[10][11][12] Current hypotheses suggest that the removal of excess protein-bound toxins in the extracorporeal circuit is likely to regenerate the native albumin, thereby enhancing its functional capacity so that it may be able to transport and detoxify more toxins. Contrary to this existing hypothesis, albumin dialysis using MARS did not improve the measured functional capacity of the patient's circulating albumin.…”

“…One such device that is commercially available is the Molecular Adsorbents Recirculating System (MARS) (Gambro, Lund, Sweden) and studies using this device show beneficial pathophysiological and clinical effects particularly in reducing the severity of hepatic encephalopathy with small studies also showing possible survival benefit in liver failure patients. [10][11][12] However, at present, detailed functional characteristics of the different binding sites in cirrhosis have not been determined. The overall aim of this study was to perform a detailed qualitative and quantitative assessment of the functional capacity of albumin in patients with liver disease of varying severities and to determine whether these alterations could be used as a marker of disease severity and prognosis.…”

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

“…However, significant differences in survival were found at day 90 (albumin 69.2% versus saline 40.0%; P = 0.02) suggesting that the development of HE may identify a subgroup of patients with advanced cirrhosis that may benefit from the administration of albumin. 114 Albumin dialysis has also been studied in a randomized controlled trial in patients with HE and advanced cirrhosis, and found to be effective for the treatment of HE, 115 however the benefits of albumin dialysis appear to be independent of changes in ammonia level or cytokines. 116 An albumin replacement system with a novel endotoxin ligation (ARSeNEL) component has been developed and tested in a porcine ALF model.…”

Extracorporeal liver support

“…44 Currently, the Molecular Adsorbent Recirculating System (MARS ® ) is the only extracorporeal liver support device that has proven to be effective in improving severe (grade 3 and 4) hepatic encephalopathy by a prospective randomized multi-center study. 45 In short, patients with end stage chronic liver disease (MELD score around 30, CTP score above 10) and intractable severe coma (HE grade 3 and 4, Glasgow Coma Scale around 7) who did not respond to prior conventional therapy were randomized to either additional daily MARS ® therapy or continuation of standard therapy only.…”