Is the molecular adsorbent recirculating system the answer for children with acute liver failure?

Abstract

See Article on Page 369 Children with acute liver failure (ALF) are among those highest at risk for death without the intervention of liver transplantation. Unfortunately, there continues to be a donor organ shortage, so not all children who could benefit from liver transplantation have timely access to this lifesaving therapy. As a result, extracorporeal liver‐support systems have been developed to address this issue. Several different systems, including cell‐based and non–cell‐based systems, have been used in an attempt to support the failing liver to either recover liver function or bridge the patient to transplantation.1 One system that has been used for more than 10 years, predominantly in Europe and Asia, is the Molecular Adsorbent Recirculating System (MARS).2 This system, originally developed in Germany, consists of 2 circuits. The first circuit is composed of human serum albumin in contact with a patient's blood through a semipermeable membrane and filters that clean the albumin after it has removed toxins from the patient's blood. The second circuit consists of a dialysis machine that cleans the albumin in the first circuit before it is recirculated to the semipermeable membrane coming in contact with the patient's blood. There are 2 sorbent columns in the system: an activated charcoal column and an anion exchanger. MARS has 510(k) approval from the US Food and Drug Administration for the treatment of drug overdoses and poisoning and has been available in the United States since 2005.3 It is required that the drug or chemical be dialyzable (in an unbound form) and be bound by charcoal and/or ion‐exchange resins. Notably, the US Food and Drug Administration has stated that MARS is not indicated as a bridge to liver transplantation because its safety and efficacy have not been demonstrated in clinical randomized controlled trials. The standard treatment for ALF involves supportive care that focuses on bridging patients to either transplantation or spontaneous recovery. The etiologies of ALF in children are not the same as those in adults with ALF, so drawing conclusions from adult data may be inappropriate.4 No large, prospective, multicenter randomized controlled trial has been performed with non–cell‐based systems in children. Most reports on the use of MARS in children are case reports or small case series.5 In this issue of Liver Transplantation, Lexmond et al.11 from the Netherlands describe their experience with MARS in treating 20 children in need of high‐urgency liver transplantation over the course of 10 years. The authors conclude that MARS therapy was relatively safe in these sick subjects; that serum bilirubin, creatinine, ammonia, and bile acid levels significantly decreased; and that 80% of these selected children survived long enough to undergo liver transplantation. The authors clearly acknowledge that their study, though large by pediatric standards, was not randomized, and that drawing any significant conclusions is difficult. No survival benefit could be demonstrated statistically. They advocate large, prospective trials and registration studies to answer important questions about pediatric ALF. They support strategies to increase the acquisition of high‐quality donor organs to improve the survival of children with ALF. One issue not mentioned in this article is the cost associated with MARS treatment. MARS therapy is costly.12 In the current climate of cost containment, financial aspects are an important consideration. Without a demonstrated statistically significant survival benefit, it is unlikely that insurers will be willing to pick up the costs of a single treatment, let alone repeated treatments, with MARS. Although MARS therapy has been available for more than a decade, there have been no randomized controlled trials of its use in children. Who is responsible for appropriately studying this potentially lifesaving therapy? Is it the responsibility of the manufacturer? Is it the responsibility of pediatric hepatologists or pediatric intensivists? Do government agencies have an ethical and moral responsibility to determine the safety and efficacy of the system? Should insurers insist on data? How long should it take to acquire the necessary data to assess the safety and efficacy of this system in children? I do not have the answers to these questions, but I believe that the time has come to get the data necessary to prove whether MARS has utility or not. I hope that multicenter randomized controlled trials will be inaugurated to answer important questions about the efficacy of MARS in children.