分子吸附再循环系统治疗肝衰竭多脏器功能不全

目的 评价分子吸附再循环系统(MARS)对肝衰竭合并多脏器功能不全(MODS)患者的治疗作用和机制。方法 24例肝衰竭合并MODS患者进行了60次6～24 h的MARS治疗。结果 MARS治疗可有效清除白蛋白结合毒素和水溶性毒素,降低一氧化氮(NO)及肿瘤坏死因子-α,白细胞介素-6、-8,和γ干扰素等细胞因子水平,改善肝性脑病、肾功能、呼吸功能以及血流动力学紊乱,序贯性脏器衰竭评估(SOFA)的计分由9.72±1.89降至6.98±2.34,24例危重肝衰竭患者中9例痊愈出院或接受肝移植,总存活率为37.5％。结论 MARS人工肝支持系统对肝衰竭合并MODS有肯定的治疗作用,其疗效除与全面清除肝衰竭蓄积的毒素外,尚与降低NO及细胞因子水平有关。     

Reduction of Elevated Cytokine Levels in Acute/Acute‐on‐Chronic Liver Failure Using Super‐Large Pore Albumin Dialysis Treatment: An In Vitro Study

The removal of small water soluble toxins and albumin‐bound toxins in acute liver failure patients (ALF) or acute‐on‐chronic liver failure (AocLF) patients has been established using extracorporeal liver support devices (e.g. Molecular Adsorbents Recirculating System; MARS). However, reduction of elevated cytokines in ALF/AocLF using MARS is still not efficient enough to lower patients' serum cytokine levels. New membranes with larger pores or higher cut‐offs should be considered in extracorporeal liver support devices based on albumin dialysis in order to address these problems, as the introduction of super‐large pore membranes could counterbalance high production rates of cytokines and further improve detoxification in vivo. Using an established in vitro two compartment albumin dialysis model, three novel membranes of different pore sizes were compared with the MARS Flux membrane for cytokine removal and detoxification qualities in vitro. Comparing the membranes, no improvement in the removal of water soluble toxins was found. Albumin‐bound toxins were removed more efficiently using novel large (Emic2) to super‐large pore sized membranes (S20; HCO Gambro). Clearance of cytokines IL‐6 and tumor necrosis factor‐α was drastically improved using super‐large pore membranes. The Emic2 membrane predominantly removed IL‐6. In vitro data suggest that the usage of larger pore sized membranes in albumin dialysis can efficiently reduce elevated cytokine levels and liver failure toxins. Using large to super‐large pore membranes might exert effects on patients' serum cytokine levels. Combined with increased detoxification this could lead to higher survival in ALF/AocLF. Promising membranes for clinical evaluation have been identified.     

Early Molecular Adsorbents Recirculating System Treatment of Amanita Mushroom Poisoning

Acute poisoning due to ingestion of hepatotoxic Amanita sp. mushrooms can result in a spectrum of symptoms, from mild gastrointestinal discomfort to life‐threatening acute liver failure. With conventional treatment, Amanita phalloides mushroom poisoning carries a substantial risk of mortality and many patients require liver transplantation. The molecular adsorbent recirculating system (MARS) is an artificial liver support system that can partly compensate for the detoxifying function of the liver by removing albumin‐bound and water‐soluble toxins from blood. This treatment has been used in acute liver failure to enable native liver recovery and as a bridging treatment to liver transplantation. The aim of the study is to evaluate the outcome of 10 patients with Amanita mushroom poisoning who were treated with MARS. The study was a retrospectively analyzed case series. Ten adult patients with accidental Amanita poisoning of varying severity were treated in a liver disease specialized intensive care unit from 2001 to 2007. All patients received MARS treatment and standard medical therapy for mushroom poisoning. The demographic, laboratory, and clinical data from each patient were recorded upon admission. The one‐year survival and need for liver transplantation were documented. The median times from mushroom ingestion to first‐aid at a local hospital and to MARS treatment were 18 h (range 14–36 h) and 48 h (range 26–78 h), respectively. All 10 patients survived longer than one year. One patient underwent a successful liver transplantation. No serious adverse side‐effects were observed with the MARS treatment. In conclusion, MARS treatment seems to offer a safe and effective treatment option in Amanita mushroom poisoning.     

Successful use of Molecular Absorbent Regenerating System (MARS) dialysis for the treatment of fulminant hepatic failure in children accidentally poisoned by toxic mushroom ingestion

Background: Acute liver failure (ALF) as a result of mushroom poisoning is associated with a high mortality (particularly in children), despite optimal medical therapy (OMT), including charcoal haemoperfusion and haemodiafiltration. MARS is a new, cell‐free, extracorporeal liver assistance method utilizing an albumin dialysate for the removal of albumin‐bound toxins. Methods: We describe the first series in the literature (also first MARS treatments in Romania) with ALF because of mushroom poisoning in children (M/F = 2/4, age = 7–16 years). Liver function was evaluated pre‐MARS and 15‐min post‐MARS, 24 h following each treatment and 30 days post‐MARS. Findings: All patients had severe hepatic dysfunction: hepatic encephalopathy (HE; four grade II, one grade III, one grade IV), ALT = 4082 (3400–5600) IU/L, bilirubin = 6.3 2 - 10 ) mg/dL, prothrombin time (PT) = 52.5 (23–141) s. MARS was uneventful and well‐tolerated. Two 6‐h sessions per patient were performed with a similar immediate impact on liver tests: mean drop in ALT of ?33 and ?35%, respectively, and in bilirubin of ?39 and ?36%, respectively. ALT levels 24 h following MARS‐1, remained unchanged but continued to drop by a further ?28% following MARS‐2. By contrast, all patients had a significant rebound in bilirubin (+39%) 24 h following MARS‐1; however, following MARS‐2 a rebound was seen only in two cases (+220%). PT improved by 37% after MARS‐1 and normalized in four patients after MARS‐2. Outcome: Four patients survived and completely recovered the hepatic function. Negative prognostic markers: lack of complete correction of PT, continuous rebound and increase in bilirubin, and lack of improvement in HE post‐MARS‐1. Survival in six well‐matched cases, treated by OMT = 0/6 (P < 0.05). Conclusions: MARS is a safe and highly effective depurative therapy in children with ALF. Survival is predicted only by the impact/results of the initial MARS sessions and not by any of the baseline parameters.     

An Australian experience with the molecular adsorbents recirculating system (Mars)

The molecular adsorbents recirculating system (MARS) is a form of artificial extracorporeal liver support which has the potential to remove substantial quantities of albumin-bound toxins postulated to contribute to the pathogenesis of liver cell damage, hemodynamic instability and multi-organ failure in patients with acute liver failure and acute-on-chronic liver failure (AoCLF). We assessed the efficacy of MARS therapy in a cohort of patients with severe liver damage unresponsive to intensive medical therapy. MARS therapy was instituted late in the clinical course of six patients with severely impaired liver function refractory to intensive medical therapy, including four with AoCLF precipitated by sepsis and two with liver dysfunction due to sepsis in the absence of pre-existing chronic liver disease. Outcome measures included markers of hemodynamic stability, renal function, serum bilirubin and bile acid levels, arterial ammonia levels, the arterial ketone body (acetoacetate/beta-hydroxybutyrate) ratio, hepatic encephalopathy grade and the plasma disappearance rate of indocyanine green. The rates of discharge from the intensive care unit and in-hospital mortality were determined. Our findings suggest that MARS treatment might be associated with some clinical efficacy even in patients with advanced multi-organ dysfunction occurring in the setting of severe liver damage and in whom treatment is instituted late in the clinical course. However, the overall survival rate (1/6; 17%) was poor. More data obtained from larger cohorts of patients enrolled in randomized controlled studies will be required in order to identify categories of liver failure patients who might benefit most from MARS treatment and to ascertain the most appropriate timing of intervention.     

Is It Possible to Gain Extra Waiting Time to Liver Transplantation in Acute Liver Failure Patients Using Albumin Dialysis?

Hepatic encephalopathy (HE)‐associated brain edema is a common cause of death in acute liver failure (ALF). Molecular Adsorbent Recirculating System (MARS) albumin dialysis detoxifies endogenous and exogenous toxins from blood and improves HE. In this study we assessed the effect of MARS on increasing the length of time available while waiting for liver graft. Thirty‐seven patients with ALF who received a high‐urgent liver transplant (LTx) were divided into three groups according to the amount of histological necrosis in the explanted liver: group I = 100% necrosis; group II = 80–99% necrosis; group III = less than 80% necrosis. MARS was used continuously until LTx. Median time (range) on MARS treatment prior to LTx in groups I–III was 7 days (2–26), 6 days (1–17), and 5 days (1–15), and the median time on the waiting list was 5 days (1–11), 3 days (0–13), and 1 day (0–12), respectively. The HE grade prior to and after MARS was similar in all groups. In two patients the HE grade decreased during MARS treatment, even though the explanted liver showed a complete lack of viable cells. Overall 30‐day and one‐year survival were 97% and 92%, respectively, without differences between the three groups. In ALF patients the liver cell damage progressed to total or near total necrosis of the liver when the waiting time was prolonged. Yet, with MARS treatment some patients with total hepatic necrosis showed an absence of encephalopathy. With MARS treatment some patients might be able to wait longer for a LTx with good results.     

MARS therapy in critically ill patients with advanced malignancy: a clinical and technical report

Abstract Background/methods: Molecular Adsorbent Recirculating System (MARS) was used in three consecutive critically ill patients at the Singapore General Hospital with advanced malignancy and acute liver failure (ALF). Case 1 was a male patient with hepatocellular carcinoma (HCC) for which initial right hepatectomy was followed by left hepatectomy 5 months later for recurrent HCC. The postoperative course following second surgery was complicated by severe methicillin‐resistant Staphylococcus aureus (MRSA) sepsis, mild azotaemia and subacute cholestatic liver failure. MARS was used thrice in this patient. Case 2 was a female patient with advanced acute lymphoblastic leukaemia (ALL) with postbone marrow transplantation (BMT) acute haemolytic–uraemic syndrome (HUS) secondary to cyclosporin A (Cy A), cytomegalovirus (CMV) infection, severe nosocomial pneumonia, acute renal failure (ARF) treated with continuous haemofiltration and acute veno‐occlusive disease resulting in Budd–Chiari syndrome. The latter precipitated ALF. MARS was instituted twice. Case 3 was a male patient with advanced, refractory Hodgkin's disease previously treated with multiple courses of chemotherapy. ALF developed secondary to acute viral hepatitis B flare. He was given a trial of MARS once in the ICU. All the three patients eventually died. Results: Mean MARS intradialytic systemic pressures were as follows: systolic pressure range was 95 ± 17 to 128 ± 17 mmHg and diastolic pressure range was 51 ± 5 to 67 ± 7 mmHg. Pressure at albumin dialysate exit point from dialyser 1 (Ae) ranged from 253 ± 11 to 339 ± 15 mmHg and that at albumin dialysate entry point into dialyser 1 (Aa) ranged from 142 ± 11 to 210 ± 6 mmHg. Ultrafiltration (UF) was 633 ± 622 mL over mean treatment duration of 6.3 ± 0.9 h with a total heparin dose of 1583 ± 817 IU. Coagulation status pre‐ and 6‐h post‐MARS was similar: aPTT (P = 0.116) and platelet count (P = 0.753). There were no bleeding complications or circuit thromboses. MARS had a significant de‐uraemization effect (pre‐ and post‐MARS serum creatinine and urea: P = 0.046 and 0.028, respectively) but did not significantly attenuate blood lactate, ammonia or total bilirubin levels. Albumin dialysate (Ae ? Aa) urea and creatinine concentrations appeared to be sharply attenuated after 6 h of MARS. In contrast, the removal of total bilirubin by albumin dialysate from the blood compartment appeared to plateau after 4 h of continuous MARS operation. Conclusions: MARS was well‐tolerated in critically ill patients with advanced and complicated cancer. Low‐dose heparin was safe and did not compromise MARS circuit integrity. Although MARS had a significant de‐uraemization effect, this appeared to be limited by the duration of MARS operation. Our data suggested that such a limit was reached earlier for total bilirubin. More data are needed to confirm the present findings and further delineate the saturation limit of MARS for different toxins that accumulate in ALF. This would affect the optimal duration of MARS therapy.     

First clinical experience with Molecular Adsorbent Recirculating System (MARS) in six patients with severe acute on chronic liver failure

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.     

Molecular adsorbent recirculating system treatment for patients with liver failure: the Hong Kong experience.

BACKGROUND: The molecular adsorbent recirculating system (MARS) is an extracorporeal liver dialysis system that allows selective removal of bilirubin and other albumin-bound toxins. We reported here our experience with the use of this technique for management of liver failure at Queen Mary Hospital, Hong Kong. METHODS: From December 2002 to 2004, a total of 74 MARS sessions were performed on 22 patients. The cause of liver failure included acute liver failure (n = 2), acute on chronic liver failure (n = 12), posthepatectomy liver failure (n = 4), and posttransplantation allograft failure (n = 4). RESULTS: MARS treatment showed significant reduction in total bilirubin level, serum ammonia level and blood urea, and nitrogen (P < 0.001 for all three parameters). Five patients (22.7%) were able to bridge to transplantation and one patient (4.5%) made a spontaneous recovery. The 30-day mortality rate was 72.7%. CONCLUSIONS: Our results indicated that MARS can effectively improve serum biochemistry and is suitable for temporarily supporting patients with liver failure where transplantation is not immediately available. There is, however, no clear evidence showing that MARS can increase survival, improve the chance of transplantation or assist liver regeneration. Future studies in the form of randomized-controlled trials are crucial to characterize the true potential of this treatment.     

MARS treatment in posthepatectomy liver failure

Abstract Posthepatectomy liver failure (PHLF) is a dramatic complication following extensive liver resection or liver resection in a compromised liver, leading to death in 80% of cases. Molecular Adsorbent Recirculating System (MARS) is able to extract water and protein bound toxins out of the blood in liver failure patients. This paper describes the initial experience in the Netherlands using the MARS liver assist device in five patients with PHLF. In all patients, improvement of biochemical parameters was observed during MARS treatment along with clinical improvement in three patients. One patient survived. No clear guidelines for MARS treatment and prognostic factors for outcome after MARS treatment with regard to this patient group are available. In this paper, a MARS treatment regimen for PHLF is suggested based on literature and our own experience.     

Predictive Criteria for the Outcome of Patients With Acute Liver Failure Treated With the Albumin Dialysis Molecular Adsorbent Recirculating System

The aim of this study was to evaluate the improvement of prognostic parameters after treatment with the molecular adsorbent recirculating system (MARS) in patients with fulminant hepatitis (FH). The parameters conducive to a positive prognosis include: Glasgow Coma Scale (GCS) score ≥11, intracranial pressure (ICP) <15 mm Hg or an improvement of the systolic peak flow of 25–32 cm/s via Doppler ultrasound in the middle cerebral artery, lactate level <3 mmol/L, tumor necrosis factor‐α <20 pg/mL, interleukin (IL)‐6 <30 pg/mL, and a change in hemodynamic instability from hyperkinetic to normal kinetic conditions, and so define the timing (and indeed the necessity) of a liver transplant (LTx). From 1999 to 2008 we treated 45 patients with FH with MARS in the intensive care unit of our institution. We analyzed all the parameters that were statistically significant using univariate analysis and considered the patients to be candidates for inclusion in a multivariate logistic regression analysis. Thirty‐six patients survived: 21 were bridged to liver transplant (the BLT group) and 15 continued the extracorporeal method until native liver recovery (the NLR group) with a positive resolution of the clinical condition. Nine patients died before transplantation due to multi‐organ failure. We stratified the entire population into three different groups according to six risk factors (the percentage reduction of lactate, IL‐6 and ICP, systemic vascular resistance index values, GCS <9, and the number of MARS treatments): group A (0–2 risk factors), group B (3–4 risk factors), and group C (5–6 risk factors). Analyzing the prevalence of these parameters, we noted that group A perfectly corresponded to the NLR group, group B corresponded to the BLT group, and group C was composed of patients from the non‐survival group; thus, we were able to select the patients who could undergo a LTx using the predictive criteria. For patients with an improvement of neurological status, cytokines, lactate, and hemodynamic parameters, LTx was no longer necessary and their treatment continued with MARS and standard medical therapy.     

分子吸附循环系统治疗肝衰竭52例

目的 评价分子吸附循环系统(MARS)治疗重型乙型肝炎肝衰竭的疗效,并探讨其机理。 方法 应用MARS对重型乙型肝炎肝衰竭的患者在常规治疗的基础上进行每次6～8h的MARS治疗,治疗前后检测各种有毒物质的改变,并与血浆置换组、常规治疗组进行比较。 结果 52例重型乙型肝炎肝衰竭患者。经MARS治疗后,临床症状及体征明显改善,血胆红素、血氨、尿素氮、芳香氨基酸、内毒素、白细胞介素-6、肿瘤坏死因子水平明显降低,治疗前后分别为(521.5±122.5)μmol/L和(360.1±81.2)μmol/L、(227.1±66.7)μg/ml和(105.0±42.0)μg/ml、(12.3±5.4)mmol/L和(6.4±2.4)mmol/L、(37.0±24.0)×10-3g/L和(23.0±16.0)×103g/L、(1.4±0.9)Eu/ml和(0.2±0.2)Eu/ml、(10.1±1.3)pg/ml和(5.7±1.0)pg/ml、(28.5±11.6)μg/ml和(1 7.9±7.8)μg/ml,t值为2.303～4.702,P<0.05或0.01。MARS与血浆置换在治疗后清除胆红素差异无显著性,而治疗后72 h血胆红素反跳,血浆置换组明显高于MARS组。总体存活率:MARS治疗组50％(26/52),血浆置换组45％(9/20),而常规治疗组存活率40.5％(17/42),MARS治疗组与常规治疗组相比较差异有显著性,u=3.024,P<0.01。 结论 MARS人工肝治疗肝衰竭,可明显提高其存活率,无明显不良反映。     

Effect of treatment with the Molecular Adsorbents Recirculating System on arterial amino acid levels and cerebral amino acid metabolism in patients with hepatic encephalopathy

Background: Liver failure is associated with low concentrations of branched‐chain amino acids and high concentrations of most other amino acids. In this study the effect of treatment with the Molecular Adsorbents Recirculating System (MARS) on arterial amino acid levels and cerebral amino acid metabolism was examined in patients with severe hepatic encephalopathy. Methods: The study included seven patients with hepatic encephalopathy from fulminant hepatic failure (FHF) and five patients with hepatic encephalopathy from acute‐on‐chronic liver failure (AoCLF). Cerebral blood flow and cerebral arteriovenous differences in amino acids were measured before and after 6?h of treatment with MARS. Results: During MARS treatment, the total arterial amino acid concentration decreased by 20% from 8.92?±?7.79?mmol/L to 7.16?±?5.64?mmol/L (P?P?Conclusions: MARS treatment tends to normalize the arterial amino acid concentrations in patients with hepatic encephalopathy. Even though the overall reduction in plasma amino acids and improvement in amino acid dysbalance may well be beneficial, it was not accompanied by any immediate improvement in cerebral amino acid metabolism in patients with FHF or AoCLF.     

分子吸附再循环治疗慢加急性肝衰竭疗效观察

目的观察分子吸附再循环系统(MARS)在慢加急性肝衰竭中的治疗作用。方法比较15例慢加急性肝衰竭患者MARS治疗前后肝、肾功能,血氨、凝血酶原活动度及Glasgow评分等指标。结果 MARS人工肝治疗后,患者体内的血清总胆红素水平较治疗前明显下降,差异有统计学意义(P0.05)。但血清转氨酶、尿素氮、肌酐、凝血酶原活动度无显著变化(P0.05),治疗前后Glasgow评分差异无统计学意义(P0.05)。结论 MARS人工肝是一项安全的治疗措施,其对清除胆红素为代表的蛋白结合毒素效果明显,但并不能改善慢加急性肝衰竭患者肝性脑病的程度及总体预后,其意义在于为肝移植患者赢得时间。     

Targeting Albumin Binding Function as a Therapy Goal in Liver Failure: Development of a Novel Adsorbent for Albumin Dialysis

Liver failure results in impaired hepatic detoxification combined with diminished albumin synthesis and is associated with secondary organ failure. The accumulation of liver toxins has shown to saturate albumin binding sites. This was previously demonstrated by an in vitro test for albumin binding capacity (ABiC) that has shown to inversely correlate with the established MELD (Model for End-Stage Liver Disease) score. In this study, we introduced a new adsorbent material for albumin dialysis treatments that improves albumin binding capacity. The new charcoal adsorbent was developed by an evolutionary test schedule. Batch testing of charcoals was performed as steady-state experiments. The charcoal reflecting the highest increase in albumin binding capacity was then introduced to kinetic models: Perfusion tests were designed to evaluate adsorption capacity and kinetics for liver failure marker toxins. A dynamic recirculation model for liver failure was used for upscaling and comparison against conventional MARS adsorbents as the gold standard in an albumin dialysis setting. Batch tests revealed that powdered activated Hepalbin charcoal displayed the highest ABiC score. Hepalbin charcoal also demonstrated higher adsorptive capacity and kinetics for liver failure marker toxins as determined by perfusion tests. These findings translated to tests of upscaled adsorbents in a dynamic model for liver failure: upscaled Hepalbin adsorbent removes bile acids, direct bilirubin and indirect bilirubin significantly better than MARS adsorbents and significantly increases ABiC. The novel adsorbent Hepalbin offers a significant improvement over both MARS adsorbents concerning liver failure marker toxin removal and ABiC improvement.     

MARS: a futile tool in centres without active liver transplant support.

BACKGROUND AND AIM: Studies on Molecular Adsorbent Recycling Systems (MARS) showed inconclusive survival benefits. PATIENTS AND METHOD: We evaluated the efficacy of MARS for patients with either acute liver failure (ALF) or acute-on-chronic liver failure (AoCLF) at our centre, from February 2002 till April 2006 retrospectively. RESULTS: Fifty ALF patients underwent median (range) three (1-10) sessions of MARS. Acute exacerbations of chronic hepatitis B (n=26) and drug-induced liver injury (n=12) were the commonest causes. Living donors were available in 6, 2 paediatric patients underwent left lobe and four adults underwent right lobe living donor liver transplant. Among the 44 ALF patients without a suitable living donor, one underwent deceased donor liver transplant and survived, another 19-year-old male with acute exacerbations of chronic hepatitis B recovered without transplant, and the rest died. Twenty-six had AoCLF and underwent four (1-10) MARS sessions. Sepsis (n=16) and upper gastrointestinal bleeding (n=4) were the commonest precipitating factors. None had a suitable living or deceased donor, suitable for transplantation during their hospitalization. Only one of 26 AoCLF patients survived the hospitalization, but the survivor died of sepsis 1 month later. CONCLUSION: In this non-randomized study, survival after MARS was related to the availability of transplant, and in patients where living or deceased donor transplant was unavailable, MARS was of little benefit. Randomized-controlled trials on MARS((R)) are urgently needed to clarify its clinical utility.     

Eosinophils involved in fulminant hepatic failure are associated with high interleukin‐6 expression and absence of interleukin‐5 in liver and peripheral blood

Background/Aims: Although eosinophils are considered to play an important role in the pathogenesis of various parasitic, allergic and autoimmune digestive diseases, their role in fulminant hepatic failure (FHF) is unknown. Our contribution was to identify and quantify eosinophils and cytokine levels [interleukin (IL)‐6, IL‐5 and macrophage inflammatory protein (MIP)‐1α] in liver parenchyma and peripheral blood from FHF patients at pre‐ and post‐transplantation steps. Methods: Histochemical methods were used to identify/quantify eosinophils in liver samples. Liver and plasma cytokine levels were quantified using immunofluorescence methods. Results: Fulminant hepatic failure patients showed a high number of intrahepatic eosinophils concomitant with an increased expression of IL‐6, besides the IL‐6‐positive eosinophils associated with the lack of IL‐5. Also, an increased number of eosinophils and soluble IL‐6 and MIP‐1α with a low expression of IL‐5 in peripheral blood at the pretransplantation step was observed. Conclusions: The increased number of intrahepatic eosinophils, besides the high production of IL‐6, may be involved in liver dysfunction. In addition, the low presence of IL‐5 in liver and peripheral blood may represent a particular pattern of eosinophil behaviour in human liver failure, which may also involve MIP‐1α. Further ex vivo studies are necessary to evaluate the specific role of eosinophils in FHF.     

Molecular Adsorbent Recirculating System (MARS®) removal of piperacillin/tazobactam in a patient with acetaminophen‐induced acute liver failure

The objective of this study was to illustrate the pharmacokinetic removal of piperacillin/tazobactam in an anuric patient on Molecular Adsorbent Recirculating System (MARS^®). The patient was a 32‐year‐old woman who presented to a medical intensive care unit with acute liver failure secondary to an acetaminophen overdose. While awaiting transplant, she was started on MARS therapy as a bridge to liver transplant and empirically started on piperacillin/tazobactam therapy. MARS is an extracorporeal hemofiltration device, which incorporates a continuous venovenous hemofiltration (CVVHD) machine linked to an albumin‐enriched dialysate filter to normalize excess electrolytes, metabolic waste, and protein‐bound toxins. In addition to protein‐bound waste, MARS removes water‐soluble, low molecular‐weight molecules. The patient received piperacillin/tazobactam 4.5 g infused intravenously over 3 h. A steep decline in serum levels occurred between hours 4 and 6 while MARS continued and no antibiotic was infused. The elimination rate constant (k_e) for the removal of piperacillin in this patent was 0.453 h^?1 and the half‐life (λ) was 1.53 h. The k_e was 2.9‐fold higher than with CVVHD alone and the λ was 3.7‐fold shorter. Low levels of piperacillin are achieved during MARS therapy, but in the treatment of more resistant organisms, such as Pseudomonas aeruginosa, these low levels may not be adequate to achieve bactericidal activity. Drug levels following a standard infusion of 30 min would likely be even lower. Formalized pharmacokinetic studies of piperacillin/tazobactam removal in patients on MARS therapy are necessary to make clear dosing recommendations.     

Review article: clinical experience with Prometheus

Prometheus is a new extracorporeal liver support device which facilitates the combined removal of both albumin-bound and water-soluble toxins based upon the method of fractionated plasma separation and adsorption (FPSA). The pilot trial included 11 patients with acute-on-chronic liver failure and concomitant renal failure. Prometheus therapy was found to be safe except for a reversible decrease of blood pressure. In three patients, clotting of the secondary system occurred. Prometheus treatment significantly improved blood levels of protein-bound (conjugated bilirubin, bile acids, ammonia) and water-soluble (creatinine, urea) substances. Thus, Prometheus might be a new therapeutic option in patients with severe hepatorenal syndrome. Furthermore, there is some preliminary experience with Prometheus in the treatment of refractory cholestatic pruritus and in successful bridging to liver transplantation. In order to compare extraction capacities of Prometheus and the molecular adsorbent recirculating system (MARS), five patients were crossover-treated with both systems. Prometheus resulted in significantly higher reduction ratios of bilirubin, ammonia and urea. Another study closely monitored whether the device causes an unselective removal. Neither important cytokines nor coagulation factors were found to be removed. In conclusion, Prometheus seems to be a new therapeutic option in artificial liver support. A significant improvement of the biochemical milieu was already observed after two treatments. The potential to remove protein-bound and water-soluble substances has been shown without signs of a significant unselective removal.