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      Artificial liver support systems: what is new over the last decade?

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          Abstract

          The liver is a complex organ that performs vital functions of synthesis, heat production, detoxification and regulation; its failure carries a highly critical risk. At the end of the last century, some artificial liver devices began to develop with the aim of being used as supportive therapy until liver transplantation (bridge-to-transplant) or liver regeneration (bridge-to-recovery). The well-recognized devices are the Molecular Adsorbent Recirculating System™ (MARS™), the Single-Pass Albumin Dialysis system and the Fractionated Plasma Separation and Adsorption system (Prometheus™). In the following years, experimental works and early clinical applications were reported, and to date, many thousands of patients have already been treated with these devices. The ability of artificial liver support systems to replace the liver detoxification function, at least partially, has been proven, and the correction of various biochemical parameters has been demonstrated. However, the complex tasks of regulation and synthesis must be addressed through the use of bioartificial systems, which still face several developmental problems and very high production costs. Moreover, clinical data on improved survival are conflicting. This paper reviews the progress achieved and new data published on artificial liver support systems over the past decade and the prospects for these devices.

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          Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial.

          Acute-on-chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n=95) or to standard therapy (SMT) (n=94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per-protocol (PP) analysis (PP population n=156). Up to 10 6-8-hour MARS sessions were scheduled. The main endpoint was 28-day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28-day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44-1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P=0.02) and bilirubin (P=0.001) and a more frequent improvement in HE (from grade II-IV to grade 0-I; 62.5% versus 38.2%; P=0.07) was observed in the MARS group. Severe adverse events were similar.
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            Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin.

            We have recently shown that nitric oxide or authentic endothelium-derived relaxing factor generated in a biologic system reacts in the presence of specific protein thiols to form S-nitrosoprotein derivatives that have endothelium-derived relaxing factor-like properties. The single free cysteine of serum albumin, Cys-34, is particularly reactive toward nitrogen oxides (most likely nitrosonium ion) under physiologic conditions, primarily because of its anomalously low pK; given its abundance in plasma, where it accounts for approximately 0.5 mM thiol, we hypothesized that this plasma protein serves as a reservoir for nitric oxide produced by the endothelial cell. To test this hypothesis, we developed a methodology, which involves UV photolytic cleavage of the S--NO bond before reaction with ozone for chemiluminescence detection, with which to measure free nitric oxide, S-nitrosothiols, and S-nitrosoproteins in biologic systems. We found that human plasma contains approximately 7 microM S-nitrosothiols, of which 96% are S-nitrosoproteins, 82% of which is accounted for by S-nitroso-serum albumin. By contrast, plasma levels of free nitric oxide are only in the 3-nM range. In rabbits, plasma S-nitrosothiols are present at approximately 1 microM; 60 min after administration of NG-monomethyl-L-arginine at 50 mg/ml, a selective and potent inhibitor of nitric oxide synthetases, S-nitrosothiols decreased by approximately 40% (greater than 95% of which were accounted for by S-nitrosoproteins, and approximately 80% of which was S-nitroso-serum albumin); this decrease was accompanied by a concomitant increase in mean arterial blood pressure of 22%. These data suggest that naturally produced nitric oxide circulates in plasma primarily complexed in S-nitrosothiol species, principal among which is S-nitroso-serum albumin. This abundant, relatively long-lived adduct likely serves as a reservoir with which plasma levels of highly reactive, short-lived free nitric oxide can be regulated for the maintenance of vascular tone.
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              Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature.

              A large number of taxonomies are used to rate the quality of an individual study and the strength of a recommendation based on a body of evidence. We have developed a new grading scale that will be used by several family medicine and primary care journals (required or optional), with the goal of allowing readers to learn one taxonomy that will apply to many sources of evidence. Our scale is called the Strength of Recommendation Taxonomy. It addresses the quality, quantity, and consistency of evidence and allows authors to rate individual studies or bodies of evidence. The taxonomy is built around the information mastery framework, which emphasizes the use of patient-oriented outcomes that measure changes in morbidity or mortality. An A-level recommendation is based on consistent and good-quality patient-oriented evidence; a B-level recommendation is based on inconsistent or limited-quality patient-oriented evidence; and a C-level recommendation is based on consensus, usual practice, opinion, disease-oriented evidence, or case series for studies of diagnosis, treatment, prevention, or screening. Levels of evidence from 1 to 3 for individual studies also are defined. We hope that consistent use of this taxonomy will improve the ability of authors and readers to communicate about the translation of research into practice.
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                Author and article information

                Contributors
                juanfeira@outlook.com
                Karim.Bendjelid@hcuge.ch
                Journal
                Ann Intensive Care
                Ann Intensive Care
                Annals of Intensive Care
                Springer International Publishing (Cham )
                2110-5820
                15 November 2018
                15 November 2018
                2018
                : 8
                : 109
                Affiliations
                [1 ]ISNI 0000 0001 0721 9812, GRID grid.150338.c, Intensive Care Unit, , Geneva University Hospitals, ; 4 Rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland
                [2 ]ISNI 0000 0001 2322 4988, GRID grid.8591.5, Faculty of Medicine, , University of Geneva, ; Geneva, Switzerland
                [3 ]Geneva Hemodynamic Research Group, Geneva, Switzerland
                Article
                453
                10.1186/s13613-018-0453-z
                6238018
                30443736
                882134b3-ef19-4088-980d-ea8bac36f8ee
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 5 July 2018
                : 7 November 2018
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Emergency medicine & Trauma
                acute liver failure,acute on chronic liver failure,artificial liver support,albumin dialysis,mars,prometheus,spad,fpsa

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