ArticleLiterature Review

Sorbent-based artificial liver devices: Principles of operation, chemical effects and clinical results

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Abstract

Devices for support of patients with liver failure are of two types: bioartificial livers and artificial livers. Bioartificial livers include hepatocytes in bioreactors to provide both excretory and synthetic liver functions. Artificial livers use nonliving components to remove toxins of liver failure, supply nutrients and macromolecules. Current artificial liver devices use columns or suspensions of sorbents (including adsorbents and absorbents) to selectively remove toxins and regenerate dialysate, albumin-containing dialysate, plasma filtrate or plasma. This article reviews three artificial liver devices. Liver Dialysis uses a suspension of charcoal and cation exchangers to regenerate dialysate. MARS uses charcoal and an anion exchanger to regenerate dialysate with albumin. Prometheus uses neutral and anion exchange resins to regenerate a plasma filtrate containing albumin and small globulins. We review the operating principles, chemical effects, clinical effects and complications of use of each type of artificial liver. These devices clearly improve the clinical condition of patients with acute or acute-on-chronic liver failure. Further randomized outcome studies are necessary to prove clinical outcome benefit of the artificial liver support devices, and define what types of patients appear most amenable to therapy.

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... Alternate designs would fix the sorbent in different positions in the dialysate stream. As is the case with plasma separation, sorbent addition to the dialysate stream has been considered more extensively for the treatment of liver failure than kidney failure [77]. In one design, part of the dialysate stream would be passed over a sorbent and then added to the fresh dialysate being pumped past the dialysis membrane (Fig. 2b). ...
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The adequacy of hemodialysis is now assessed by measuring the removal of the single-solute urea. The urea clearance provided by contemporary dialysis is a large fraction of the blood flow through the dialyzer and therefore cannot be increased much further. Other solutes however likely contribute more than urea to the residual uremic illness suffered by hemodialysis patients. We here review methods which could be employed to increase the clearance of nonurea solutes. We will separately consider the clearances of free low-molecular-mass solutes, free larger solutes, and protein-bound solutes. New clinical studies will be required to test the extent to which increasing the clearance on nonurea solutes with these various characteristics can improve patients' health.
... As is the case with plasma separation, sorbent addition to the dialysate stream has been considered more extensively for the treatment of liver failure than kidney failure. 56 In one design, part of the dialysate stream would be passed over a sorbent and then added to the fresh dialysate being pumped past the dialysis membrane ( Fig 2B). The effect would be to greatly increase the effective dialysate flow for solutes taken up by the sorbent and increase their clearances by keeping their concentrations low in the dialysate compartment. ...
Article
The adequacy of hemodialysis is now assessed by measuring the removal of the single solute urea. The urea clearance provided by current dialysis methods is a large fraction of the blood flow through the dialyzer, and therefore cannot be increased much further. Other solutes which are less effectively cleared than urea may however contribute more to the residual uremic illness suffered by hemodialysis patients. We here review a variety of methods which could be employed to increase the clearance of such non-urea solutes. New clinical studies will be required to test the extent to which increasing solute clearances improves patients' health.
... Unfortunately, the increased need for organ transplantation is met by a lack of organ donors. Some surgical techniques such as living donor procedure [1] or cadaveric donor liver split sharing between two recipients [2]; as well as bioartificial hepatic support [3] can partly alleviate this shortage. ...
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We aimed at reviewing the various uses of Nude mouse for the development of liver deficiency models and evaluation of efficacy of hepatic cell xenotransplantation. The first part records the large range of liver deficiency models that can be developed in Nude mice: surgical partial hepatectomy, acute toxic liver deficiency, chronic cirrhosis, and transgenic liver injury. The second part tackles the outcome of rat hepatocyte as well as human cell transplantation, both mature hepatocyte and hepatic progenitor, into Nude mouse submitted to liver injury. Results are discussed and compared to other available immunodeficient mouse models. The issue of humanized liver creation is also addressed. Altogether, these results show that Nude mouse appears to be a suitable small animal model to expand our insight into liver cell engraftment and regeneration.
... Liver Dialysis (HemoCleanse, Lafayette, Indiana, USA) -originally called Biologic-DT -was developed by Ash et al. 11 12 The patient's blood is moved from a central vein via a single lumen multi-holed catheter using a push-pull procedure, resulting in a flow rate of 200-250 ml/min. 13 Simultaneously, a 2-litre suspension of powdered activated charcoal and cation exchange resin (TU 7) is pumped from a sorbent bag through the dialysate side of a flatplate membrane dialyser (TU 4: 5 kDa molecular weight cut-off (MWCO) cellulosic membranes) and returned to the sorbent bag. ...
Article
Liver failure is associated with high morbidity and mortality without transplantation. There are two types of device for temporary support: artificial and bioartificial livers. Artificial livers essentially use non-living components to remove the toxins accumulated during liver failure. Bioartificial livers have bioreactors containing hepatocytes to provide both biotransformation and synthetic liver functions. We review here the operating principles, chemical effects, clinical effects and complications of both types, with specific attention paid to bioartificial systems. Several artificial support systems have FDA marketing authorisation or are CE labelled, but the improvement they provide in terms of patient clinical outcome has not yet been fully demonstrated. At present, different bioartifical systems are being investigated clinically on the basis of their promises and capacity to provide and replace most liver functions. However, important issues such as cost, cell availability, maintenance of cell viability and functionality throughout treatment, and regulatory issues, as well as difficult challenges, including implementing cell-housing devices at the patient's bedside on an emergency basis, have delayed their appearance in intensive care units and on the market. Bioreactors are, nevertheless, when combined with artificial components, a pragmatic approach for future treatment of liver failure.
Chapter
Treating diseases involving the kidney, liver and immune systems often requires a good grasp of blood purifying technologies, specifically membranes and adsorbents. This is the first book to elucidate the role of biomaterials in blood purification technologies. Starting with a fundamental introduction on bio/haemocompatibility of materials, the reader will move on to learn about the membranes used for blood purification in key environments, namely the liquid–liquid environment (e.g. the artificial kidney) and will look at haemodialysis and materials therein, to liquid–gas environments (e.g. the artificial lung), before moving on to chapters delving into hybrid artificial organs and smart membranes. The next part of the book looks at adsorbents, including immunoadsorbents and bionic adsorbents. The book ends with the prospect of blood purification materials. Edited by a leader in the field, this book is a novel and comprehensive analysis of blood purification materials. It is essential reading for those working in biomaterials science and engineering.
Article
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Article
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Chapter
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Chapter
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Article
Introduction: Molecular adsorbent recirculating system (MARS) for albumin liver dialysis has been used as a bridge to liver transplantation in patients with fulminant hepatic failure (FHF). This review examines the available data on its clinical use, its technical aspects and present gaps in knowledge. Methods: Peer-reviewed journals and monographs on the subject were covered. Results: FHF is associated with elevation in various substances including bilirubin, ammonia, lactate, free fatty acids and aromatic amino acids. Some of these toxic metabolites, such as ammonia and bilirubin, are believed to be central to the clinical manifestations of hepatic encephalopathy and acute renal failure. MARS ameliorates both biochemical and clinical manifestations of FHF by removing both water-soluble and protein-bound toxins. Among the benefits of MARS is the attenuation of severe cerebral oedema and raised intracranial pressure found in FHF, possibly through reduction in high concentrations of these toxins. Although MARS has been shown to be useful in FHF, its clinical efficacy in subfulminant hepatic failure and less severe forms of acute liver failure (ALF) remains uncertain. The current literature also suggests that it may be beneficial to treat cases of acute-on-chronic liver failure (AoCLF). Deranged systemic chemistries can be similarly ameliorated, but the impact of MARS on the natural history of AoCLF remains uncertain. The difficulty lies in being able to accurately quantify residual liver function and variability in the course of acute intercurrent events. The broader question is whether MARS can favourably change the natural history of ALF and FHF. For this, large multi-centre, randomised controlled trials are needed. Furthermore, it is also uncertain how hepatic excretory-assist devices, such as MARS, compare with bio-artificial liver-assist devices which have both synthetic and excretory hepatic functions in ALF treatment in intensive care unit patients. Nevertheless, MARS has proven to be a valuable homeostatic tool that may be useful in restoring the biochemical and clinical status quo in much the same way that continuous veno-venous haemofiltration and mechanical ventilation provide temporary artificial organ support while these organs are in distress. This is the evolving concept of multi-organ support therapy. Other major unresolved issues with MARS include the timing of initiation of albumin liver dialysis, the clinical and/or biochemical parameters to base this decision on, the intensity of MARS therapy (continuous versus intermittent) and the saturation capacity of the system for different metabolites in intermittent MARS. Conclusions: MARS is an effective and, thus far, safe homeostatic tool in treating FHF. More studies are needed to delineate its role as a homeostatic tool in less severe forms of ALF, including that which occurs in multi-organ failure and in AoCLF. Other studies need to focus on the optimal timing of initiation of and intensity of MARS albumin liver dialysis. The larger issue is to compare MARS with bio-assist liver devices in treating the whole spectrum of ALF.
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Patients with severe acute alcoholic hepatitis develop multiple organ failure which is associated with production of inflammatory cytokines and a poor prognosis. The aim of the present pilot study was to evaluate the effects of the BioLogic-DT sorption-suspension dialyser in patients with severe acute alcoholic hepatitis. Ten patients with encephalopathy (grade II-IV) were entered into the study, 5 received treatment with the BioLogic-DT for 6 hours daily for 3 days and 5 received conventional treatment as controls. The system was biocompatible with no adverse effects on blood pressure or platelet counts, factor V, fibrinogen or antithrombin III. No bleeding episodes were observed even with the use of small doses of heparin. After 3 days, blood ammonia was lower in the BioLogic-DT treated patients than in the controls, although blood lactate was higher. There were slight increases in plasma TNF and IL-8 during treatment over and above the higher levels present initially, possibly as a result of activation of white cells in the extracorporeal circuit. The further development of the BioLogic-DT dialyser with the addition of a plasma treatment module capable of removing cytokines would be worth evaluating in acute alcoholic hepatitis.
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AIM: To evaluate whether treatment with the Prometheus® system significantly affects cytokines, coagulation factors and other plasma proteins. METHODS: We studied nine patients with acute-on-chronic liver failure and accompanying renal failure. Prometheus® therapy was performed on 2 consecutive days for up to 6 h in all patients. Several biochemical parameters and blood counts were assessed at regular time points during Prometheus® treatment. RESULTS: We observed a significant decrease of both protein-bound (e.g. bile acids) and water-soluble (e.g. ammonia) substances after Prometheus® therapy. Even though leukocytes increased during treatment (P 0.5). Further, antithrombin 3, factor II and factor V plasma levels did not decrease during Prometheus® therapy (all P > 0.5), and the INR remained unchanged (P = 0.4). Plasma levels of total protein, albumin, and fibrinogen were also not altered during Prometheus® treatment (all P > 0.5). Finally, platelet count did not change significantly during therapy (P = 0.6). CONCLUSION: Despite significant removal of protein-bound and water-soluble substances, Prometheus® therapy did not affect the level of cytokines, coagulation factors or other plasma proteins. Thus, the filters and adsorbers used in the system are highly effective and specific for water-soluble substances and toxins bound to the albumin fraction.
Article
In hepatorenal syndrome (HRS), renal insufficiency is often progressive, and the prognosis is extremely poor under standard medical therapy. The molecular adsorbent recirculating system (MARS) is a modified dialysis method using an albumin-containing dialysate that is recirculated and perfused online through charcoal and anion-exchanger columns. MARS enables the selective removal of albumin-bound substances. A prospective controlled trial was performed to determine the effect of MARS treatment on 30-day survival in patients with type I HRS at high risk (bilirubin level,15 mg/dL) compared with standard treatment. Thirteen patients with cirrhosis with type I HRS were included from 1997 to 1999. All were Child's class C, with Child-Turcotte-Pugh scores of 12.4 ± 1.0, United Network for Organ Sharing status 2A, and total bilirubin values of 25.7 ± 14.0 mg/dL. Eight patients were treated with the MARS method in addition to hemodiafiltration (HDF) and standard medical therapy, and 5 patients were in the control group (HDF and standard medical treatment alone). None of these patients underwent liver transplantation or received a transjugular intrahepatic portosystemic shunt or vasopressin analogues during the observation period. In the MARS group, 5.2 ± 3.6 treatments (range, 1 to 10 treatments) were performed for 6 to 8 hours daily per patient. A significant decrease in bilirubin and creatinine levels (P < .01) and increase in serum sodium level and prothrombin activity (P < .01) were observed in the MARS group. Mortality rates were 100% in the control group at day 7 and 62.5% in the MARS group at day 7 and 75% at day 30, respectively (P < .01). We conclude that the removal of albumin-bound substances with the MARS method can contribute to the treatment of type I HRS.
Article
Episodic (acute) type C hepatic encephalopathy (AHE) fails to respond to 5 days of medical therapy in 10–30% of patients and carries a 10–30% mortality rate. We prospectively studied extracorporeal liver support for AHE failing to respond to medical therapy to assess its safety and efficacy and the role of anticoagulation.MethodsA series of patients with cirrhosis and AHE failing to respond to at least 24 h of medical therapy underwent a maximum of three 6-h charcoal-based hemodiabsorption (Liver Dialysis Unit) treatments. A standard anticoagulation protocol, with heparin dosing based on activated clotting time (ACT) determinations, heparin dose–response curve, and target ACT of 275–300 s, was developed. Therapy was terminated if patients met a predetermined clinical response, deteriorated, or underwent transplantation.ResultsEighteen patients with grade 2–4 AHE despite 5.9 ± 3.9 days of medical therapy underwent a mean of 1.6 treatments. In 2.6 ± 1.9 days, 16 patients (88.9%) improved to less than grade 2 HE or achieved at least a 50% hepatic encephalopathy index (HEI) reduction. Median mental status (grade 2 vs 1, p < 0.05) and HEI (0.634 ± 0.194 vs 0.363 ± 0.263, p < 0.005) improved significantly. Survival was 94.4% and 72.2% at 5 and 30 days, respectively. Use of our developed anticoagulation protocol resulted in less platelet (14.2% ± 2.8% vs 32.5% ± 5.8%, p < 0.005) and fibrinogen consumption (12.1% ± 3.5% vs 43.3% ± 8.6%, p < 0.0005) and blood product use (6.2 ± 1.8 vs 19.0 ± 5.6 units, p < 0.05) compared with treatments according to manufacturer's guidelines.Conclusions Charcoal-based hemodiabsorption treatments in which a standardized anticoagulation protocol is used is safe and effective treatment for AHE not responding to standard medical therapy.
Article
: Acute liver failure after hepatic surgery is still plaqued with high mortality rate. Recently, a liver dialysis system (MARS®) that allows detoxification of albumin-bound substances and may hereby support liver regeneration and patient's recovery has been developed. In the present study, we report our experiences with MARS® dialysis in patients with liver failure after hepatic resection or transplantation. Between September 1999 and January 2001, five patients were treated with MARS® (2–5 courses). Though beneficial effects such as improvement of encephalopathy and renal function as well as reduced bilirubin levels were recorded during MARS® therapy, only one patient survived. Neither significant technical problems nor adverse effects occurred by using MARS® dialysis. We conclude that in surgical patients, acute liver failure is usually part of a complicated clinical course affecting multipleorgan systems. Thus, it is difficult to determine the specific influence of MARS® on patient's outcome. However, beneficial effects observed in our patients justify its continuous use and may stimulate further evaluation in controlled studies with surgical patients.
Article
: Extracorporeal liver support using the MARS recently has shown remarkable results in several trials. This study aims to extend the basis for analyses by making available the worldwide data with help of an international registry. One hundred and seventy six patients were analysed, main indications are acute-on-chronic liver failure (56%), acute liver failure (22%), primary graft dysfunction (15%), liver failure post liver surgery (4%) and miscellaneous (3%). The predicted survival within the first group based on a mean MELD score of 30.4 pts. and a mean Child score of 12.6 pts. was quite limited. The data suggest an improved survival accompanied by significant improvements of hepatic encephalopathy, mean arterial pressure, serum bilirubin level, creatinine, urea, albumin, INR, ammonia and MELD score. The results are confirming observations of other trials before which have shown MARS therapy to be an effective and safe extracorporeal liver support in liver failure.
Article
For patients with hepatorenal syndrome improvement of survival and of multiple organ functions was proven by the use of MARS (Molecular Adsorbent Recirculating System). MARS is a modified dialysis using an albumin-containing dialysate, that is recirculated and on-line perfused through charcoal and anion exchanger columns. It allows the selective removal of albumin-bound substances.Despite advances in medical therapy and technology, the prognosis of patients with cardiogenic shock remains poor. Mortality rates as high as 80%, often caused by persistent multiple organ failure are unacceptable. Therefore we conducted a prospective, randomized, and controlled study with patients suffering from hypoxic liver failure following cardiogenic shock after cardiac surgery. Main aim was to prove that MARS improves survival.We report a interim analysis of the 17 patients, who were included between 8/00 and 8/01 in our study. Eight patients formed the MARS group (MG) and 9 were in the non-MARS group (NMG). All patients had bilirubin levels >8mg/mL. The risk profile of both groups was almost identical. The MG received MARS for 3 consecutive days — if bilirubin was still >6mg/dl afterwards MARS was continued. The NMG received conventional therapy.Results: There were 6 survivors in the MG, compared to 1 survivor in the NMG (P=0.015). Moreover Bilirubin levels declined faster to lower levels in the MG.Conclusion: Despite the limited number of patients included in this interim analysis, MARS can be recommended for patients with acute, hypoxic liver failure as it might significantly improve survival.
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Fifteen patients with acute deterioration of liver function, high serum ammonia, and an average coma level of 3.9 (of 4) were treated for 8-12 hrs daily with a system that uses the membranes of a cellulosic plate dialyzer to pump blood through a single access at 200-225 ml/min, and includes a sorbent suspension as dialysate. Neurologic status of the patients was declining before treatment, but significantly improved during each treatment and over the course of 1-12 (average, 4) treatments. Diastolic blood pressure and pulse rate normalized. For half the patients, treatment with the BioLogic-DT system served as a bridge to liver transplant or liver recovery. (C)1991 American Society of Artificial Internal Organs
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Article
Acetaminophen overdose is the leading cause for calls to Poison Control Centers (>100,000/year) and accounts for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year. Data from the U.S. Acute Liver Failure Study Group registry of more than 700 patients with acute liver failure across the United States implicates acetaminophen poisoning in nearly 50% of all acute liver failure in this country. Available in many single or combination products, acetaminophen produces more than $1 billion dollars in annual sales for Tylenol products alone. It is heavily marketed for its safety compared to nonsteroidal analgesics. By enabling self-diagnosis and treatment of minor aches and pains, its benefits are said by the Food and Drug Administration to outweigh its risks. It still must be asked: Is this amount of injury and death really acceptable for an over-the-counter pain reliever? (HEPATOLOGY 2004;40:6–9.)
Article
Five patients with severe heart disease developed cardiogenic shock of more than 24 hours' duration. As a sequela to the shock, severe liver affection was demonstrated. Serum aspartate aminotransferases and serum lactate dehydrogenases showed very high activities. The prothrombin-proconvertin index was reduced to less than 25% of the normal. Four of the patients were jaundiced. The condition gave rise to some differential diagnostic problems. Liver biopsies were available from four of the patients, and histological examination of an autopsy specimen of the liver was performed in each case. The liver histology showed centrilobular necrosis and haemorrhage in all patients. It seems that centrilobular fibrosis develops later in the condition. The pathogenesis of this liver affection is probably hypoxic injury to the centrilobular areas of the liver lobule due to reduced liver blood flow.
Article
Fifteen patients with acute deterioration of liver function, high serum ammonium, and an average coma level of 3.9 were identified. Eleven of the patients were on respirator support, and eleven had kidney failure pursuant to the liver failure. The patients were treated for 8-12 hours daily with the BioLogic-DT system, in which membranes of a cellulosic plate dialyzer actively pump blood through a single access at over 200 ml/min, and the dialysate contains a suspension of powdered activated charcoal (300,000 square meters surface area) and cation exchanger (160 meq capacity). No anticoagulant was used. In spite of the declining condition of the patients prior to treatment, there was a statistically significant improvement in neurologic status during individual treatments, and a positive trend over 1-12 (average four) daily treatments. Four patients recovered liver function and another four improved enough to receive a liver transplant operation. The BioLogic-DT system appears to be safe in treatment of patients with hepatic insufficiency and coma. The neurologic improvement of these patients indicates that many toxins of hepatic failure are dialyzable across cellulosic membranes and bound by charcoal.
Article
Fifteen patients with acute deterioration of liver function, high serum ammonia, and an average coma level of 3.9 (of 4) were treated for 8-12 hrs daily with a system that uses the membranes of a cellulosic plate dialyzer to pump blood through a single access at 200-225 ml/min, and includes a sorbent suspension as dialysate. Neurologic status of the patients was declining before treatment, but significantly improved during each treatment and over the course of 1-12 (average, 4) treatments. Diastolic blood pressure and pulse rate normalized. For half the patients, treatment with the BioLogic-DT system served as a bridge to liver transplant or liver recovery.
Article
In patients with acute liver failure and hepatic coma, an increase in the abnormal "middle molecules" seen on the chromatograms of the sera is suspected of playing an etiologic role in the coma. A pilot study of continuous hemofiltration using a high-performance membrane was conducted in 16 such patients in an attempt to decrease the serum levels of the middle molecules. The procedure was used alternately with plasma exchange. High-performance liquid chromatography showed a notable removal of the substances in the filtrates and a sequential removal from the serum by hemofiltration. Eight (50%) of the 16 patients had amelioration in level of consciousness and were weaned successfully from hemofiltration. Although only three of the 16 patients survived the acute illness, 13 others lived an average of 15 days and five patients survived greater than 3 wk. While the continuous removal of middle molecules from the serum may not reverse liver failure, this procedure used in conjunction with plasma exchange may provide a means of life support, e.g., for patients awaiting a liver transplant.
Article
One hundred thirty-seven patients with fulminant hepatic failure were entered into two controlled trials of charcoal hemoperfusion carried out concurrently. In trial A, 75 patients with grade 3 encephalopathy were randomized to receive 5 or 10 h of hemoperfusion daily. Overall survival rates for the two groups were similar (51.3% vs. 50.0%) as was the frequency of major complications including cerebral edema and renal failure. In trial B, in which 62 patients with established grade 4 encephalopathy on admission were randomized to a no-perfusion group or to have 10 h of hemoperfusion daily, overall survival rates for the two groups were again similar (39.3% and 34.5%, respectively). There was in both trials a significant relationship between survival and etiology quite independent of the use or duration of hemoperfusion. Thus, percentage survival for the acetaminophen-overdose cases was 52.9%, for hepatitis A 66.7%, for hepatitis B 38.9%, for presumed non-A, non-B hepatitis 20%, and for halothane or drug reaction 12.5%. Within the etiologic subgroups survival was also influenced by the three major complications that developed, being inversely related to their frequency and combination, except in the non-A, non-B hepatitis and halothane or drug reaction subgroups, which had a high mortality throughout. In the latter cases particularly, orthotopic liver transplantation merits early consideration and in the group with better "intrinsic" survival (acetaminophen, hepatitis A and B) intensive management of complications (rather than charcoal hemoperfusion) would appear to be of major importance.
Article
Hyperfibrinolysis may complicate the clinical course of liver cirrhosis. The aim of this study was to evaluate if, in cirrhosis, hyperfibrinolysis is primary or secondary to intravascular clotting activation and if endotoxemia is associated with activation of clotting and/or the fibrinolytic system. Clotting, fibrinolytic indexes, and endotoxemia were studied in 41 cirrhotic patients and 20 healthy subjects. Twenty-seven cirrhotic patients (66%) had high plasma levels of prothrombin fragment F1 + 2, a marker of thrombin generation. Nineteen patients had elevated values of D-dimer, a marker of fibrinolysis in vivo. All patients with high values of D-dimer also had high values of prothrombin fragment F1 + 2. Endotoxemia was elevated in patients with severe liver failure and significantly correlated to prothrombin fragment F1 + 2. Thirty patients were treated for 7 days either with standard therapy (n = 15) or with standard therapy plus nonabsorbable antibiotics (n = 15). Although standard therapy did not significantly change laboratory indexes, a significant reduction of endotoxemia, prothrombin fragment F1 + 2, and D-dimer was found in those patients who received the combined treatment. This study shows that, in cirrhotic patients, hyperfibrinolysis is not a primary phenomenon but occurs as a consequence of clotting activation and that endotoxemia might play a pathophysiological role.
Article
Hemodiabsorption is a selective chemical removal process during which blood passes through dialysis membrane packages surrounded by a suspension of fine sorbent particles. The BioLogic-DT system contains charcoal and cation exchangers in a suspension that passes through dialysate spaces of a cellulosic membrane plate dialyzer. The system has proven effective in treatment of patients with serious drug overdose and has demonstrated positive effects in treatment of stage 4 coma due to hepatic failure. Recently, the charcoal in this system has been preloaded with branch chain amino acids to return these acids to patients while aromatic amino acids are removed. Further improvements include addition of osmotically active agents to the priming fluid and sorbent to increase blood oncotic pressure and transfer of ascitic fluid to blood while ultrafiltration transfers fluid out of the blood. Clinical testing of these improvements is now beginning in patients with ascites and encephalopathy due to chronic hepatic insufficiency and cirrhosis. Future improvements will include protein permeable membranes to increase removal of protein-bound toxins and addition of hepatic cells downstream from the hemodiabsorption unit.
Article
A new artificial liver support system (ALSS) consisting of plasma exchange (PE) in combination with hemodiafiltration (HDF) using high-performance membranes of polymethyl methacrylate (PMMA) and cellulose triacetate (CTA) was developed to efficiently remove middle molecules from plasma and treat fulminant hepatic failure (FHF) complicated by the onset of hepatic coma. Twenty-seven patients with FHF due to viral hepatitis, two with type A (HA), nine with type B (HB), and 16 with type non-A, non-B (NANB) underwent therapy with this new ALSS over the last five years. Three patients with an exacerbation of chronic HB and 15/16 with type NANB hepatitis were treated with interferon (IFN) also. Of these, 25 patients (92.6%) regained consciousness and 15 (55.6%) [1/2 (50%) with type A, 6/9 (66.7%) with type B and 8/16 (50%) with type NANB hepatitis] survived. Including four patients who survived with intensive care and plasma exchange alone, 19/31 (61.3%) patients survived. Because of its biocompatibility, both survivors and nonsurvivors could be sustained with the ALSS without complications for long periods (19.3 days for the survivors and 32.4 days for nonsurvivors). With this ALSS the ability to sustain life for such prolonged periods allows hepatic regeneration to occur and result in patient survival. It is anticipated that this new ALSS will not only be of value in cases of fulminant hepatic failure but that it may also play a role in sustaining life for those awaiting liver transplantation.
Article
The liver is the primary site of synthesis of most coagulation and fibrinolytic proteins, and also plays a role in the clearance of hemostasis factors and their degradation products. In acute liver failure, these functions are severely disturbed, and the risk of hemorrhage is increased. Following a brief summary of the physiology of hemostasis, this review describes the nature and frequency of hemostatic abnormalities in acute liver failure. These abnormalities include quantitative and qualitative platelet defects, impaired synthesis and clearance of the coagulation factors and related inhibitory proteins, and enhanced fibrinolysis. Disseminated intravascular coagulation may also play a role, although this syndrome is difficult to distinguish from changes due to the failure of hepatic synthesis and clearance alone. At present, management options are limited to support with blood products, although pharmacological manipulation of the coagulation and fibrinolytic systems represent a potential area for future study.
Article
The prevalence and characteristics of acetaminophen-associated liver injury in hospitalized patients are not well defined. We identified patients hospitalized for excessive acetaminophen ingestion at an urban county hospital over a 40-month period (1992 to 1995) and reviewed their medical records to determine the incidence and clinical features of the ingestions and their outcomes. Of the 71 patients studied, 50 were classified as having taken acetaminophen during suicide attempts and 21 as having accidentally poisoned themselves while attempting to relieve pain. The suicidal patients had ingested almost twice as much acetaminophen as those in the accidental-overdose group (median, 20 vs. 12 g; P=0.009). Among the patients for whom data were available, 63 percent of those in the accidental-overdose group and 25 percent of those in the suicidal group had chronic alcohol abuse (P=0.009). The patients in the accidental-overdose group more often had severe liver necrosis (aminotransferase levels, >3500 IU per liter; 52 percent vs. 14 percent; P=0.002), and were more likely to have hepatic coma (33 percent vs. 6 percent, P=0.006). There were four deaths (19 percent) in the accidental-overdose group and one (2 percent) in the suicidal group (P=0.04). Five patients -- three in the accidental-overdose group and two in the suicidal group -- had ingested 4 g of acetaminophen or less. Acetaminophen ingestion accounted for 12 percent of all patients hospitalized with overdoses (71 of 589) and 40 percent of patients with acute liver failure (10 of 25) during the study period. In an urban county hospital, patients hospitalized with acetaminophen toxicity related to accidental misuse had higher rates of morbidity and mortality than those who attempted suicide, even though the latter had taken more acetaminophen. A higher frequency of chronic alcohol abuse among the patients with accidental overdoses may be one explanation.
Article
Conducted at the University of California, Los Angeles, this randomized, prospectively controlled study was designed to measure the effects of a hemodiabsorption device in the treatment of 11 patients with hepatic failure and stage III to IV encephalopathy. The results of 5 days of treatment with the hemodiabsorption device were compared with those of standard intensive care procedures. The BioLogic-DT System, a simple sorbent-based system, demonstrated a slight improvement in the neurologic status of patients, a significant improvement in the physiologic status of patients, and an improved outcome for treated patients as opposed to nontreated patients.
Article
Patients with severe acute alcoholic hepatitis develop multiple organ failure which is associated with production of inflammatory cytokines and a poor prognosis. The aim of the present pilot study was to evaluate the effects of the BioLogic-DT sorption-suspension dialyser in patients with severe acute alcoholic hepatitis. Ten patients with encephalopathy (grade II-IV) were entered into the study, 5 received treatment with the BioLogic-DT for 6 hours daily for 3 days and 5 received conventional treatment as controls. The system was biocompatible with no adverse effects on blood pressure or platelet counts, factor V, fibrinogen or antithrombin III. No bleeding episodes were observed even with the use of small doses of heparin. After 3 days, blood ammonia was lower in the BioLogic-DT treated patients than in the controls, although blood lactate was higher. There were slight increases in plasma TNF and IL-8 during treatment over and above the higher levels present initially, possibly as a result of activation of white cells in the extracorporeal circuit. The further development of the BioLogic-DT dialyser with the addition of a plasma treatment module capable of removing cytokines would be worth evaluating in acute alcoholic hepatitis.
Article
The use of xenogenic or genetically engineered cell types in bioartificial liver support systems requires separation methods between the patients' blood and the liver support bioreactors that guarantee the sufficient transfer of pathophysiologically relevant substances but prevent complications. The present paper describes a new membrane separation system that is nearly impermeable to proteins but enables the exchange of water soluble and protein bound toxins by a special membrane and a recycled protein containing dialysate. Because the full range of toxins in hepatic failure has still not been identified, the value of this membrane separation method was evaluated clinically. Thirteen patients suffering from life threatening hepatic failure who had not responded to state of the art therapy were treated with this device, the molecular adsorbent recycling system (MARS). The overall survival rate was 69%. All patients showed positive response to the therapy, indicating that the presented membrane separator combines therapeutic effectivity with the highest safety criteria for the patient by cutting the exchange of substances below the level of proteins.
Article
To review the cause, epidemiology, pathophysiology, and treatment of cardiogenic shock. A MEDLINE search of the English-language reports published between 1976 and 1998 and a manual search of bibliographies of relevant papers. Experimental, clinical, and basic research studies related to cardiogenic shock. Data in selected articles were reviewed, and relevant clinical information was extracted. Cardiogenic shock is a state of inadequate tissue perfusion due to cardiac dysfunction, most commonly caused by acute myocardial infarction. Mortality rates for patients with cardiogenic shock remain frustratingly high, ranging from 50% to 80%. The pathophysiology of cardiogenic shock involves a downward spiral: Ischemia causes myocardial dysfunction, which, in turn, worsens ischemia. Areas of nonfunctional but viable (stunned or hibernating) myocardium can also contribute to the development of cardiogenic shock. The key to achieving a good outcome is an organized approach that includes rapid diagnosis and prompt initiation of therapy to maintain blood pressure and cardiac output. Expeditious coronary revascularization is crucial. When available, emergency cardiac catheterization and angioplasty seem to improve survival. More recent developments, such as placement of coronary stents and use of glycoprotein IIb/IIIa antagonists, are promising but have not yet been well studied in patients with cardiogenic shock. In hospitals without direct angioplasty capability, stabilization with intra-aortic balloon counterpulsation and thrombolysis followed by transfer to a tertiary care facility may be the best option. Improved understanding of the pathophysiology of shock and myocardial infarction has led to improved treatment. If cardiogenic shock is managed with rapid evaluation and prompt initiation of supportive measures and definitive therapy, outcomes can be improved.
Article
In hepatorenal syndrome (HRS), renal insufficiency is often progressive, and the prognosis is extremely poor under standard medical therapy. The molecular adsorbent recirculating system (MARS) is a modified dialysis method using an albumin-containing dialysate that is recirculated and perfused online through charcoal and anion-exchanger columns. MARS enables the selective removal of albumin-bound substances. A prospective controlled trial was performed to determine the effect of MARS treatment on 30-day survival in patients with type I HRS at high risk (bilirubin level, > or =15 mg/dL) compared with standard treatment. Thirteen patients with cirrhosis with type I HRS were included from 1997 to 1999. All were Child's class C, with Child-Turcotte-Pugh scores of 12.4 +/- 1. 0, United Network for Organ Sharing status 2A, and total bilirubin values of 25.7 +/- 14.0 mg/dL. Eight patients were treated with the MARS method in addition to hemodiafiltration (HDF) and standard medical therapy, and 5 patients were in the control group (HDF and standard medical treatment alone). None of these patients underwent liver transplantation or received a transjugular intrahepatic portosystemic shunt or vasopressin analogues during the observation period. In the MARS group, 5.2 +/- 3.6 treatments (range, 1 to 10 treatments) were performed for 6 to 8 hours daily per patient. A significant decrease in bilirubin and creatinine levels (P <.01) and increase in serum sodium level and prothrombin activity (P <.01) were observed in the MARS group. Mortality rates were 100% in the control group at day 7 and 62.5% in the MARS group at day 7 and 75% at day 30, respectively (P <.01). We conclude that the removal of albumin-bound substances with the MARS method can contribute to the treatment of type I HRS.
Article
Liver failure associated with excretory insufficiency and jaundice results in an endogenous accumulation of toxins involved in the impairment of cardiovascular, kidney, and cerebral function. Moreover, these toxins have been shown to damage the liver itself by inducing hepatocellular apoptosis and necrosis, thus creating a vicious cycle of the disease. We report a retrospective cohort study of 26 patients with acute or chronic liver failure with intrahepatic cholestasis (bilirubin level > 20 mg/dL) who underwent a new extracorporeal blood purification treatment. A synthetic hydrophilic/hydrophobic domain-presenting semipermeable membrane (pore size < albumin size, 100-nm thick) was used for extracorporeal blood detoxification using dialysis equipment. The opposite side was rinsed with ligandin-like proteins as molecular adsorbents that were regenerated online using a chromatography-like recycling system (molecular adsorbent recirculating system [MARS]). Bile acid and bilirubin levels, representing the previously described toxins, were reduced by 16% to 53% and 10% to 90% of the initial concentration by a single treatment of 6 to 8 hours, respectively. Toxicity testing of patient plasma onto primary rat hepatocytes by live/dead fluorescence microscopy showed cell-damaging effects of jaundiced plasma that were not observed after treatment. Patients with a worsening of Child-Turcotte-Pugh (CTP) index before the treatments showed a significant improvement of this index during a period of 2 to 14 single treatments with an average of 14 days. After withdrawal of MARS treatment, this improvement was sustained in all long-term survivors. Ten patients represented a clinical status equivalent to the United Network for Organ Sharing (UNOS) status 2b (group A1), and all survived. Sixteen patients represented a clinical status equivalent to UNOS status 2a, and 7 of these patients survived (group A2), whereas 9 patients (group B) died. We conclude that in acute excretory failure caused by a chronic liver disease, this treatment provides a therapy option to remove toxins involved in multiorgan dysfunction secondary to liver failure.
Article
Extracorporeal detoxification has been proposed to treat patients with hepatic encephalopathy (HE) not responding to standard therapy. To investigate the biocompatibility of a cuprophane charcoal-based detoxification device, a prospective, randomized, controlled study was performed. Of 41 consecutive patients with cirrhosis and HE grade II or III who did not improve with conventional treatment, 20 patients (median age, 56 years; range, 33 to 71 years; 13 men) were randomly assigned to either ongoing conventional treatment or one additional 6-hour treatment with a sorbent suspension dialysis system. Main outcome parameters were physiological function and blood parameters of biocompatibility. In the 10 patients undergoing combined conventional and sorbent suspension dialysis treatment, blood pressure remained unchanged and body temperature and heart rate increased (P: < 0.01). Platelet count decreased (medians, from 75 to 26 g/L; P: < 0.001) and international normalized ratio increased after combined treatment (2.0 to 2.2; P: < 0.001). Three patients developed bleeding complications during treatment or shortly after. Treated patients showed increases in levels of plasma elastase (104 to 586 microg/L; P: = 0.001), tumor necrosis factor-alpha (5.4 to 7.5 pg/mL; P: = 0.04), and interleukin-6 (118 to 139 pg/mL; P: = 0.04), but not interferon-gamma and E-selectin. No changes were observed in the 10 patients treated conventionally. In conclusion, despite technical refinements compared with charcoal hemoperfusion, biocompatibility of sorbent suspension dialysis is still very limited. Clinical complications were apparently caused by blood-membrane interactions and disseminated intravascular coagulation. We suggest further developments in design and appropriate strategies of anticoagulation to improve the biocompatibility of artificial liver support.
Article
The bioartificial liver (BAL), with depurative and synthetic capacities, and the molecular absorption recycling system (MARS) characterized by the only depuration function through hybrid layers foe detoxics tied up to the albumin transportation are two different extracorporeal methods today available for the treatment of acute liver failure. The BAL using hepatocites derived from hepatoblastoma or from animals is loaded by the risk of the appearance of antibodies for the exposure to specific species antigens, in limiting the application in a long period. MARS, conditioned from the impossibility of synthesis, can be used for an illuminated time. Atm of our study is to report our experience in using MARS in three patients with acute liver failure secondary to PNF (case 1), FHF due to HBV infection (case 2), Autoimmune acute hepatitis (case 3). All patients were in the waiting list for an urgent liver transplant. The parameters of hepatic and renal function, the coagulation values, ammoniemia and albuminemia have been monitorized before and after treatment that lasted 8.1 ± 1.5 hours. The three patients were in hepatic coma and underwent to the EEG. For the lack of hepatic synthesis has always been set up substitutive therapy. Neither hemodinamic complications or variations of the albuminemia have been observed during the treatment. Patient nr. 2 has been successfully transplanted. The results of our study are reported in the table 1. We conclude that MARS treatment should be safe and that it could be used in hepatic liver failure as bridge to the liver transplantation or as artificial depurative support waiting for the recovery of normal hepatic function, as it can remove the toxic substances like ammonium and bilirubine.
Article
To test the efficacy of the molecular adsorbent recycling system (MARS) in patients with acute exacerbation of chronic liver disease. A prospective case analysis. A university-affiliated tertiary medical center. We applied MARS to treat a consecutive series of eight patients with acute exacerbation of chronic liver disease. The overall survival rate was 62.5%. All patients demonstrated improvement with regard to their degree of encephalopathy. In three patients, intracranial pressure and jugular bulb oxygen saturation decreased and cerebral perfusion pressure increased after treatment institution. Patients' hyperdynamic state was attenuated, as demonstrated by elevation of systemic vascular resistance, mean arterial pressure, and parallel reduction in cardiac index. A prompt reduction in serum ammonia, bilirubin, and lactate levels was observed. There were no complications during the treatment period. Applying MARS treatments to patients with acute exacerbation of chronic liver disease can detoxify blood, improve cerebral circulation, and reduce brain edema, as reflected by the reduction in intracranial pressure and jugular bulb oxygen saturation values in our patients. A partial reversal of the characteristic hyperdynamic circulation was also achieved. Despite our encouraging results, further testing is needed to determine the reliability of the system.
Article
The aim of this uncontrolled pilot study is to determine the effect of treatment with the molecular adsorbents recirculating system (MARS) on cerebral perfusion in patients with acute on chronic liver failure (AOCLF). In 8 patients (median age, 44 years; range, 35 to 52 years) admitted with AOCLF, a single 10-hour MARS treatment was performed. Hepatic encephalopathy (HE) was graded according to the Fogarty criteria. Changes in cerebral perfusion were determined by transcranial Doppler as mean flow velocity (V(mean)) in the middle cerebral artery. Arterial ammonia and bilirubin levels were monitored as a measure of the capability of the MARS to remove water-soluble and protein-bound toxins. During MARS treatment, HE grade improved in 3 patients and remained unchanged in 5 patients (P =.11). V(mean) increased from 42 cm/sec (range, 26 to 59 cm/sec) to 72 cm/sec (range, 52 to 106 cm/sec; P <.05), whereas arterial ammonia level decreased from 88 micromol/L (range, 45 to 117 micromol/L) to 71 micromol/L (range, 26 to 98 micromol/L; P <.05) and bilirubin level from 537 micromol/L (range, 324 to 877 micromol/L) to 351 micromol/L (range, 228 to 512 micromol/L; P <.05). In conclusion, cerebral perfusion is increased and levels of ammonia and bilirubin are reduced during MARS treatment in patients with AOCLF.
Article
The Liver Dialysis Unit (the Unit) is a liver-assist device that employs hemodiabsorption (dialysis of blood against powdered sorbents) to selectively remove numerous small molecular weight toxins of hepatic failure. The Unit has been cleared by the Food and Drug Administration and is indicated and marketed for treatment of acute hepatic encephalopathy (AHE) due to decompensation of chronic liver disease (A-on-C) or fulminant hepatic failure (FHF). Controlled, prospective, and randomized studies of liver dialysis were conducted at several centers, enrolling 56 patients with AHE, grades II-IV with or without renal and respiratory insufficiency or failure. Liver dialysis treatments were for 6 h daily, 1-5 days with similar observation periods for control patients. Physiologic status, neurologic status, and outcome (recovery of hepatic function, improvement for transplant, or death) were measured, and results were compared for treated patients versus controls for patients with A-on-C and patients with FHF. Liver dialysis resulted in physiologic and neurologic improvement of patients with AHE, regardless of etiology. Liver dialysis significantly improved the incidence of positive outcomes (recovery of hepatic function or improvement for transplant) of A-on-C patients versus controls (71.5% treated, 35.7% control, p = 0.036), but had an insignificant improvement in the outcome of patients with FHF as compared with the control group. Among the overall 31 treated patients, 51.6% survived. Outcome was not negatively affected by the presence of kidney failure or respiratory failure. The plasmafilter unit (PF-Unit) combines hemodiabsorption with push-pull sorbent-based pheresis (the PF add-on module, with powdered sorbent surrounding plasmafilters). At blood flow rates of 200 ml/min, the system clears creatinine and aromatic amino acids at 120-160 ml/min, unconjugated bilirubin at 20-40 ml/min, and cytokines at 15-25 ml/min. The PF-Unit has been tested in a few patients with hepatic failure with Grades III and IV encephalopathy, and respiratory, and kidney insufficiency. Treatment appeared to be safe, and there were no significant hematologic changes. Physiologic changes included improved blood pressure, and encephalopathy, and stable urine output. Chemical changes included a decrease in the plasma levels of bilirubin, aromatic amino acids, ammonium, creatinine, and IL-1beta. The PF add-on module adds the capability to the Unit to remove bilirubin and other strongly protein-bound toxins from treated patients and may be of clinical benefit in the management of patients with the most severe hepatic failure and encephalopathy, including patients with FHF or concomitant sepsis.
Article
An FDA-approved Phase 1 feasibility study was performed in two centers to determine the safety of the BioLogic-DTPF (detoxifier/plasma filter) system for the treatment of patients with systemic inflammatory response syndrome (SIRS). This device combines hemodiabsorption (dialysis of blood against powdered sorbents with the BioLogic-DT system) with push-pull sorbent-based pheresis (the PF add-on module). Eight adult ICU patients with both SIRS and multiple organ failure participated in the study. One 6 h treatment was planned for each patient with powdered charcoal as sorbent for 4 patients and a combination of charcoal/silica in the PF sorbent bag for 4 patients. The treatments appeared to have no negative effects in 7 patients, but 1 patient died during treatment due to progressive cardiac failure. Sepsis was resolved in 5 of the 8 patients. However, there were only 2 long-term survivors of the group. The addition of the PF module should improve the chemical function of the BioLogic-DT by allowing removal of protein-bound toxins such as cytokines. The selected patients tolerated treatment by the DTPF system well, but proof of benefit of the device remains to be proven in a Phase 2 clinical trial with randomized controls.
Article
Artificial liver support aims to prolong survival time of patients with liver failure by detoxification. Albumin as a molecular adsorbent in dialysis solution is capable of attracting even tightly albumin-bound toxins from blood into the dialysate if a specific dialysis membrane is used and if the albumin's binding sites are on-line-purified by a sorbent/dialysis-based recycling system (i.e., molecular adsorbents recycling system, or MARS). The MARS technology has been shown to remove water-soluble and albumin-bound toxins and to provide renal support in case of renal failure. Fourteen centers have reported that MARS treatment improved mental status of patients with liver failure and hepatic encephalopathy. In treating liver failure and cholestasis, MARS was associated with hemodynamic stabilization, improvement of hepatic and kidney function, and disappearance of pruritus. In hepatic failure and hepatorenal syndrome, a prospective, randomized, controlled trial of MARS treatment was able to prolong survival time significantly. MARS has been used in 26 patients with acute liver failure or primary graft dysfunction. Nineteen centers reporting on 103 patients have shown that MARS treatment is safe, easy to handle, feasible, and effective.
Article
Extracorporeal blood detoxification by sorbent therapy long has been applied in treatment of hepatic failure and encephalopathy, starting with hemoperfusion columns and more recently with the currently marketed Liver Dialysis Unit. Liver Dialysis employs hemodiabsorption (dialysis of blood against powdered sorbents including charcoal and cation exchanger) to remove selectively numerous small-molecular-weight toxins of hepatic failure. Liver Dialysis is used in treatment of acute hepatic encephalopathy (AHE) because of decompensation of chronic liver disease (A-on-C) or fulminant hepatic failure (FHF). Controlled, prospective and randomized studies of daily 6-hour Liver Dialysis have shown physiologic and neurologic improvement of patients with AHE, regardless of etiology. Liver dialysis significantly improved the incidence of positive outcomes (recovery of hepatic function or improvement for transplant) of A-on-C patients versus controls (71.5% treated, and 35.7% control, P =.036), but had an insignificant improvement in outcome of patients with FHF as compared with the control group. Other extracorporeal sorbent devices are now in clinical testing phase. The molecular adsorbent regenerating system (MARS) device employs a polysulfone high-permeability dialyzer with albumin on the dialysate side to aid transfer of protein-bound toxins such as bilirubin and bile acids across the membranes. Sorbent columns of charcoal and an anion exchanger remove hepatic toxins from the albumin dialysate, and a second dialyzer removes water-soluble toxins, such as ammonium. Clinical results of daily MARS treatments of patients with hepatic failure are similar to that of Liver Dialysis, with neurologic and physical improvement occurs in most patients with AHE, and improved outcome for patients with A-on-C. The system extends the life of patients with hepatorenal syndrome. PF-Liver Dialysis is an experimental device combining hemodiabsorption with push-pull sorbent-based pheresis with powdered sorbent surrounding plasmafilters. PF-Liver Dialysis (Hemocleanse, Inc, W. Lafayette, IN) has been tested in a few patients with hepatic failure, grade 3-4 encephalopathy, and respiratory and kidney insufficiency. Treatments appeared to be safe and resulted in marked decreases in plasma levels of bilirubin, aromatic amino acids, ammonium, creatinine, and interleukin-1beta (IL-1beta). The PF add-on module adds the capability to Liver Dialysis to remove bilirubin, bile acids, and other strongly protein-bound toxins from treated patients and may be of clinical benefit in management of patients with the most severe hepatic failure and encephalopathy, including patients with FHF or concomitant sepsis.
Article
Unlabelled: Despite recent advances in general supportive care, the mortality rate of patients with severe liver insufficiency remains high. Recently a new artificial liver support system MARS has been used for selective removal of albumin-bound toxins. Aim: To assess the safety and efficacy of MARS treatment in patients with acute on chronic liver disease (n = 5) or liver failure after extended hepatic resection (n = 1). Design/patients: Six patients, aged 34-58 years, with severe liver insufficiency (mean MELD-score 31 (range 24-35)) were treated one to 16 times with the MARS system. At baseline three patients were intubated, three were encephalopathic (HE) and three had multifactorial kidney failure requiring kidney replacement therapy. Results and conclusion: In all the patients MARS treatment significantly reduced the serum bilirubin levels. In three patients encephalopathy improved. In two patients the extracorporeal treatment precipitated a disseminated intravascular coagulation with clinically significant bleeding. Bridging to liver transplantation was possible in one patient, the other five patients died 30 days (2-74 days) after starting MARS therapy. Our case series shows that MARS treatment in general can be safely performed in patients with severe liver disease. However, in patients with an activated clotting system severe bleeding complication can be triggered and MARS treatment should be used very cautiously in these situations. MARS seems to be a promising new treatment option for patients with acute on chronic liver failure. However, carefully conducted randomized controlled trials are necessary to define its potential place in the treatment of patients with severe liver disease.
Article
The Molecular Adsorbent Recirculating System (MARS) is a novel extracorporeal technique for liver support. We report the clinical results in the first 13 patients with severe liver failure treated at our institution. Patients with acute or acute on chronic liver failure of various aetiologies were treated with varying numbers of MARS sessions of six hours duration. Mean APACHE II score was 18. In general, patients with multiple organ failure faired poorly even with MARS treatment. Five patients (38%) survived the hospitalisation. Eight patients (62%) fulfilled criteria for UNOS type I or 2 A status. Two of these patients survived. Five patients had a UNOS 2B status and three survived. In proportion, patients with severe itch, patients with primary non-function and those where MARS was used as a bridge to transplantation seemed to profit most from the treatment. The median reduction in bilirubin concentrations after the treatment period was -28.2%. In survivors, the median reduction was -37.7% and in patients who died was -15.9%. The median encephalopathy score improved from 1.7 to 0.5. The molecular adsorbent recycling system (MARS) might be lifesaving in patients with severe liver failure of different aetiologies.
Article
Patients with liver cirrhosis and a superimposed acute injury with progressive hyperbilirubinemia have a high mortality. A prospective, controlled study was performed to test whether hyperbilirubinemia, 30-day survival, and encephalopathy would be improved by extracorporeal albumin dialysis (ECAD). Twenty-four patients were studied; 23 patients had cirrhosis; 1 had a prolonged cholestatic drug reaction and was excluded from per protocol (PP) analysis. Patients had a plasma bilirubin greater than 20 mg/dL and had not responded to prior standard medical therapy (SMT). Patients were randomized to receive SMT with ECAD or without (control). ECAD was performed with an extracorporeal device that dialyzes blood in a hollow fiber dialyzer (MW cutoff < 60 kd) against 15% albumin. Albumin-bound molecules transfer to dialysate albumin that is regenerated continuously by passage through a charcoal and anion exchange column and a conventional dialyzer. ECAD was associated with improved 30-day survival (PP, 11 of 12 ECAD, 6 of 11 controls; log rank P <.05). Plasma bile acids and bilirubin decreased on average by 43% and 29%, respectively, in the ECAD group after 1 week of treatment, but not in the control group. Renal dysfunction and hepatic encephalopathy improved in the ECAD group, but worsened significantly in the control group. ECAD was safe, with adverse events being rare and identical in both groups. In conclusion, ECAD appears to be effective and safe for the short-term treatment of patients with cirrhosis and superimposed acute injury associated with progressive hyperbilirubinemia and may be useful for increasing survival in such patients awaiting liver transplantation.
Article
The mortality of patients with severe acute alcoholic hepatitis (AH) remains high, leading to interest in the use of extracorporeal liver support. The molecular adsorbents recirculating system (MARS) is a liver support device based upon a hollow fibre module in which the patient's blood is dialyzed across an albumin-impregnated membrane. The aim of this paper is to assess the safety, efficacy and feasibility of using MARS in patients with severe AH. Eight patients (all encephalopathic; hepatorenal syndrome: Type 1, five patients; Type 2, two patients) were treated with MARS. Clinical, biochemical and haemodynamic assessments were done. Five patients were discharged from hospital, and four are alive at 3 months of follow-up, compared with an estimated survival of about 20%. There were significant improvement in serum bilirubin (P=0.008), creatinine (P=0.02), prothrombin time (P=0.04), and grade of encephalopathy (P=0.05). Sustained improvements in mean arterial pressure, systemic vascular resistance and cardiac output were observed. Thrombocytopaenia was the only MARS-related adverse event observed. MARS resulted in improved liver biochemistry, cardiovascular haemodynamics, renal function and encephalopathy in patients with severe AH, with an apparent reduction in mortality. On this basis, a multi-centre, randomized clinical trial has been initiated.
Article
Artificial and bioartificial support systems may provide a "bridge" for patients with severe liver disease to recovery or transplantation. To evaluate the effect of artificial and bioartificial support systems for acute and acute-on-chronic liver failure. Randomized trials on any support system vs standard medical therapy were included irrespective of publication status or language. Nonrandomized studies were included in explorative analyses. Trials were identified through electronic searches (Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Library, MEDLINE, EMBASE, and the Chinese Medical Database), bibliographies, and contact with experts. Searches were conducted of the entire databases through September 2002. Of 528 references identified, 12 randomized trials with 483 patients were included. Eight nonrandomized studies were included in explorative analyses. Data were extracted and trial quality was assessed independently by 3 reviewers (L.L.K., J.L., B.A-N.). The primary outcome measure was all-cause mortality. Results were combined on the risk ratio (RR) scale. Random-effects models were used. Sources of heterogeneity were explored through meta-regression and stratified meta-analyses. Of the 12 trials included, 10 assessed artificial systems for acute or acute-on-chronic liver failure and 2 assessed bioartificial systems for acute liver failure. Overall, support systems had no significant effect on mortality compared with standard medical therapy (RR, 0.86; 95% confidence interval [CI], 0.65-1.12). Meta-regression indicated that the effect of support systems depended on the type of liver failure (P =.03). In stratified meta-analyses, support systems appeared to reduce mortality by 33% in acute-on-chronic liver failure (RR, 0.67; 95% CI, 0.51-0.90), but not in acute liver failure (RR, 0.95; 95% CI, 0.71-1.29). Compared with randomized trials, nonrandomized studies produced significantly larger estimates of intervention effects (P =.01). This review suggests that artificial support systems reduce mortality in acute-on-chronic liver failure compared with standard medical therapy. Artificial and bioartificial support systems did not appear to affect mortality in acute liver failure.