Extracorporeal Albumin Dialysis in Liver Failure with MARS and SPAD: A Randomized Crossover Trial.

INTRODUCTION: Liver failure is associated with hepatic and extrahepatic organ failure leading to a high short-term mortality rate. Extracorporeal albumin dialysis (ECAD) aims to reduce albumin-bound toxins accumulated during liver failure. ECAD detoxifies blood using albumin dialysis through an artificial semipermeable membrane with recirculation (molecular adsorbent recirculating system, MARS) or without (single-pass albumin dialysis, SPAD). METHODS: We performed a randomized crossover open trial in a surgical intensive care unit. The primary outcome of the study was total bilirubin reduction during MARS and during SPAD therapies. The secondary outcomes were conjugated bilirubin and bile acid level reduction during MARS and SPAD sessions and tolerance of dialysis system devices. Inclusion criteria were adult patients presenting liver failure with factor V activity <50% associated with bilirubin ≥250 µmol/L and a complication (either hepatic encephalopathy, severe pruritus, or hepatorenal syndrome). For MARS and SPAD, the dialysis flow rate was equal to 1,000 mL/h. RESULTS: Twenty crossovers have been performed. Baseline biochemical characteristics (bilirubin, ammonia, bile acids, creatinine, and urea) were not statistically different between MARS and SPAD. Both ECAD have led to a significant reduction in total bilirubin (-83 ± 67 µmol/L after MARS; -122 ± 118 µmol/L after SPAD session), conjugated bilirubin (-82 ± 61 µmol/L after MARS; -105 ± 96 µmol/L after SPAD session), and bile acid levels (-64 ± 75 µmol/L after MARS; -56 ± 56 µmol/L after SPAD session), all nondifferent comparing MARS to SPAD. CONCLUSION: A simple-to-perform SPAD therapy with equal to MARS dialysate flow parameters provides the same efficacy in bilirubin and bile acid removal. However, clinically relevant endpoints have to be evaluated in randomized trials to compare MARS and SPAD therapies and to define the place of SPAD in the liver failure care program.

A comparison among three different apheretic techniques for treatment of hyperbilirubinemia.

Liver failure is associated to high mortality due to the accumulation of protein-bound metabolites, such as bilirubin, not removed by conventional hemodialysis. Different methods can efficiently remove them, such as the molecular adsorbent recirculating system (MARS), plasma exchange (PEX), and bilirubin or plasma adsorption perfusion (PAP). No direct comparison exists between MARS, PEX and PAP, and current guidelines do not specify which method (and when) to use. We have retrospectively evaluated MARS, PEX and PAP in their effectiveness in lowering plasma bilirubin concentration, and their effects on liver and kidney function. A total of 98 patients have been recruited, which comprised 68 patients treated with PAP (177 sessions), 16 patients with PEX (41 sessions) and 11 patients with MARS (21 sessions). Bilirubin, creatinine, liver enzymes were analyzed before and after the first treatment with each technique. The three methods did not differ for bilirubin lowering efficiency, with MARS showing only slightly less effective reductions. Finally, the three techniques did not differ in the amount of change of cholinesterase, but a lower reduction in AST was found using PAP. Our retrospective observation is one of the largest case series of hepatic failure treated with bilirubin absorption. The choice of the technique cannot be based on the desired reduction in bilirubin concentration. Based on costs and duration of treatment, we suggest that PAP could be considered as a first-line approach. In case of kidney involvement, MARS remains a valuable option.

First clinical experience in 14 patients treated with ADVOS: a study on feasibility, safety and efficacy of a new type of albumin dialysis.

BACKGROUND: Liver failure (LF) is associated with prolonged hospital stay, increased cost and substantial mortality. Due to the limited number of donor organs, extracorporeal liver support is suggested as an appealing concept to "bridge to transplant" or to avoid transplant in case of recovery. ADVanced Organ Support (ADVOS) is a new type of albumin dialysis, that provides rapid regeneration of toxin-binding albumin by two purification circuits altering the binding capacities of albumin by biochemical (changing of pH) and physical (changing of temperature) modulation of the dialysate. It was the aim of this study to evaluate feasibility, efficacy and safety of ADVOS in the first 14 patients ever treated with this procedure. METHODS: Patients included suffered from acute on chronic LF (n = 9) or "secondary" LF (n = 5) which resulted from non-hepatic diseases such as sepsis. The primary endpoint was the change of serum bilirubin, creatinine and serum BUN levels before and after the first treatment with ADVOS. The Wilcoxon Signed Rank test for paired samples was used to analyze the data. RESULTS: A total of 239 treatments (1 up to 101 per patient) were performed in 14 patients (6 female, 8 male). Mean age 54 ± 13; MELD-score 34 ± 7; CLIF-SOFA 15 ± 3. Serum bilirubin levels were significantly decreased by 32% during the first session (26.0 ± 15.4 vs. 17.7 ± 10.5 mg/dl; p = 0.001). Similarly, serum creatinine (2.2 ± 0.8 vs. 1.6 ± 0.7 mg/dl; p = 0.005) and serum BUN (49.4 ± 23.3 vs. 31.1 ± 19.7 mg/dl; p = 0.003), were significantly lowered by 27% and 37%, respectively. None of the treatment sessions had to be interrupted due to side effects related to the procedure. CONCLUSION: ADVOS efficiently eliminates water- and protein-bound toxins in humans with LF. ADVOS is feasible in patients with advanced LF which is emphasized by a total number of more than 100 treatment sessions in one single patient.

Effectiveness and Safety Assessment of Citrate Anticoagulation During Albumin Dialysis in Comparison to Other Methods of Anticoagulation.

Liver failure is a serious and often deadly disease often requiring MARS (Molecular Adsorbent Recirculating System) therapy. Choosing the safe and effective method of anticoagulation during artificial liver support systems seems to be very difficult and extremely important. The aim of this study was to assess effectiveness and safety of regional anticoagulation with citrate in liver failure patients during MARS. We used a single center observational study. We analyzed 158 MARS sessions performed in 65 patients: 105 (66.5%) sessions in 41 patients with heparin anticoagulation, 40 (25.3%) sessions in 19 patients with citrate, and 13 (8%) sessions in only five patients without anticoagulation, that were excluded from part of the analysis. To determine the effectiveness of regional anticoagulation with citrate, probability of filter survival and changes in laboratory parameters were analyzed according to the applied method of anticoagulation. The safety of citrate was determined by Ca/Ca2+ ratio, acid-base balance, bleeding complications, and the need for blood product transfusions. The probability of filter survival in the citrate group was 94% and in the heparin group 82% (P = 0.204). There was no relationship between the method of anticoagulation and effectiveness of MARS therapy in lowering the levels of the analyzed parameters. Only one patient had a Ca/Ca2+ ratio higher than he safety margin. There were no statistically significant changes in pH and lactate level irrespective of anticoagulation; bicarbonate dropped significantly only in the heparin group (P = 0.03). The frequency of bleeding complications and the need for transfusions did not differ significantly between groups. Regional anticoagulation with citrate can be an effective and safe method of anticoagulation during MARS therapy, but requires attentive monitoring and further studies in liver failure patients.

Outcome of patients with cirrhosis requiring mechanical ventilation in ICU.

INTRODUCTION: Mortality rate of patients with cirrhosis admitted to the intensive care unit (ICU) and requiring mechanical ventilation varies between 60 and 91%. The aim of our study is to assess the prognosis of these patients, their 1-year outcome and to analyze predictive factors of long-term mortality. METHODS: From May 2005 to May 2011, we studied 246 consecutive patients with cirrhosis requiring mechanical ventilation either at admission or during their ICU stay. RESULTS: Alcohol was the most common etiology of the cirrhosis (69%). Bleeding related to portal hypertension (30%) and severe sepsis (33%) were the most common reasons for admission. ICU and hospital mortality were respectively 65.9% and 70.3%. Prognostic severity scores, the need for other organ support therapy, infection, and total bilirubin value at ICU admission were significantly associated with ICU mortality. Eighty-four patients (34.1%) were discharged from the ICU. Among these patients, the one-year survival was only of 32%. Logistic regression analysis, using survival at one year as the endpoint, identified two independent risk factors: the length of ventilation (odds ratio [OR] = 1.1; 95% CI, 1.0-1.2; p = 0.02) and total bilirubin at ICU discharge (OR = 1.3; 95% CI, 1.1-1.5; p = 0.006). CONCLUSION: Patients with cirrhosis admitted to the liver ICU and who required mechanical ventilation have a poor prognosis with a 1-year mortality of 89%. At ICU discharge, a total bilirubin level higher than 64.5 µmol/L and length of ventilation higher than 9 days could help the hepatologists to identify patients at risk of death in the year following the ICU discharge.

Development of high-efficiency molecular adsorbent recirculating system: preliminary report.

Molecular Adsorbent Recirculating System (MARS) is a liver support system widely employed in the treatment of liver failure. The method is normally well tolerated. To develop a liver support system combining high efficiency and tolerability, we modified the MARS albumin circuit with the insertion of double adsorption units in parallel. Four patients have been treated with this modified method (high-efficiency MARS, HE MARS): two had very high serum bilirubin and two had very high total bile acids. After a single MARS session bilirubin was reduced more with HE MARS than standard MARS (from 27.6 to 52.3% in patient A and from 27.9 to 49.1% in patient B), and bile acid reduction increased from 40 to 59.8% in patient C and from 39.9 to 60% in patient D. The results of this preliminary investigation in only a very small number of patients do support the possibility of developing a liver support system that combines good tolerability and high efficacy.

Extracorporeal detoxification for hepatic failure using molecular adsorbent recirculating system: depurative efficiency and clinical results in a long-term follow-up.

Acute liver failure and acute-on-chronic liver failure still show a poor prognosis. The molecular adsorbent recirculating system (MARS) has been extensively used as the most promising detoxifying therapy for patients with these conditions. Sixty-four patients with life-threatening liver failure were selected, and 269 MARS treatments were carried out as a bridge for orthotopic liver transplantation (OLT) or for liver function recovery. All patients were grouped according to the aim of MARS therapy. Group A consisted of 47 patients treated for liver function recovery (median age 59 years, range 23-82). Group B consisted of 11 patients on the waiting list who underwent OLT (median age 47 years, range 32-62). Group C consisted of 6 patients on the waiting list who did not undergo OLT (median age 45.5 years, range 36-54, P = 0.001). MARS depurative efficiency in terms of liver toxins, cytokines, and growth factors was assessed together with the clinical outcome of the patients during a 1-year follow-up. Total bilirubin reduction rate per session (RRs) for each MARS session was 23% (range 17-29); direct bilirubin RRs was 28% (21-35), and indirect bilirubin RRs was 8% (3-21). Ammonia RRs was 34% (12-86). Conjugated cholic acid RRs was 58% (48-61); chenodeoxycholic acid RRs was 34% (18-48). No differences were found between groups. Hepatocyte growth factor (HGF) values on starting MARS were 4.1 ng/mL (1.9-7.9) versus 7.9 ng/mL (3.2-14.1) at MARS end (P < 0.01). Cox regression analysis to determine the risk factors predicting patient outcomes showed that age, male gender, and Sequential Organ Failure Assessment score (but not Model for End-stage Liver Disease score) were factors predicting death, whereas the number of MARS sessions and the ΔHGF proved protective factors. Kaplan-Meier survival analysis was also used; after 12 months, 21.3% of patients in Group A survived, while 90.9% were alive in Group B and 16.7% in Group C (log rank = 0.002). In conclusion, MARS was clinically well tolerated by all patients and significantly reduced hepatic toxins. Better survival rates were linked to an OLT program, but patients' clinical characteristics on starting MARS therapy were the main factors predicting survival. The role of HGF should be evaluated in larger clinical trials.

[Apheresis Techniques for the Treatment of Hyperbilirubinemia in the Nephrology Unit].

Therapeutic apheresis is an important hematological and nephrological method for conditions with altered plasma composition. It is also indicated for the removal of protein-bound molecules, such as bilirubin. Several techniques can remove these compounds, such as the extracorporeal circulation molecular adsorption system (MARS), plasma exchange (PEX), and plasma adsorption and perfusion (PAP). Here we report our experience in the comparison between MARS, PEX and PAP, since current guidelines do not specify which method is the most appropriate and under which circumstances it should be used. The choice of technique cannot be based on the desired plasma bilirubin concentration, since these three techniques show similar results with a similar final outcome (exitus). In fact, PAP, PEX and MARS significantly reduce bilirubin levels, but the degree of reduction is not different among the three. Furthermore, the three techniques do not differ in the rate of cholinesterase change, while less reduction of liver transaminases was found by using PAP. MARS should be preferred in the case of renal involvement (hepatorenal syndrome with hyperbilirubinemia). PAP has the advantage of being simple and inexpensive. PEX remains an option when emergency PAP is not available, but the risk of using blood products (plasma and albumin) must be considered.

Diagnosis and management of pediatric acute liver failure: consensus recommendations of the Indian Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ISPGHAN).

Timely diagnosis and management of pediatric acute liver failure (PALF) is of paramount importance to improve survival. The Indian Society of Pediatric Gastroenterology, Hepatology, and Nutrition invited national and international experts to identify and review important management and research questions. These covered the definition, age appropriate stepwise workup for the etiology, non-invasive diagnosis and management of cerebral edema, prognostic scores, criteria for listing for liver transplantation (LT) and bridging therapies in PALF. Statements and recommendations based on evidences assessed using the modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) system were developed, deliberated and critically reappraised by circulation. The final consensus recommendations along with relevant published background information are presented here. We expect that these recommendations would be followed by the pediatric and adult medical fraternity to improve the outcomes of PALF patients.

Case Report: Efficacy of albumin dialysis for the reversal of bile cast nephropathy-induced acute kidney injury.

Background: Bile cast nephropathy (BCN) is an underdiagnosed renal complication associated with severe hyperbilirubinemia and is seen in patients with liver failure who have cholestatic complications. BCN-induced acute kidney injury (AKI) can require hemodialysis (HD), and the molecular adsorbent recirculating system (MARS) is a potentially useful therapeutic option. Case summary: A 57-year-old male presented with jaundice persisting for 1 month, with laboratory test results indicative of hyperbilirubinemia and AKI. Abdominal imaging and a biopsy confirmed biliary ductal dilation secondary to a pancreatic head mass. The patient had rapidly progressive renal failure and refractory hyperbilirubinemia, despite biliary decompression, and was started on HD. Subsequent therapy with albumin dialysis therapy using MARS was successful in reversing the AKI, the cessation of HD, and the restoration of native renal function. Conclusion: In the setting of BCN-induced AKI, timely initiation of MARS can provide a useful therapeutic strategy to reverse renal dysfunction and facilitate intrinsic renal recovery.

Kidney Outcomes Following Utilization of Molecular Adsorbent Recirculating System.

Introduction: Molecular adsorbent recirculating system (MARS) is an extracorporeal system combining conventional veno-venous hemodiafiltration and adsorption to provide rescue support in fulminant hepatic failure. Acute kidney injury (AKI) is common in patients with hepatic failure warranting continuous kidney replacement therapy (CKRT). Our primary aim was to characterize a cohort of patients who received MARS therapy and examine kidney events given the current paucity of available data. Methods: Patients initiating MARS in a tertiary care setting from January 2014 through December 2020 were assessed for treatment indications, transplantation, CKRT, kidney recovery, and death. Data was collected using the REDCAP software. Results: A total of 49 patients (67% female; 75% White) received MARS therapy with 29 patients (59%) requiring concomitant CKRT. Hepatic encephalopathy (HE) was the most common indication for MARS initiation (55%). In-hospital mortality was 41% (12/29) among patients who received CKRT versus 10% (2/20) among those not requiring CKRT (relative risk [RR] 4.15, 95% confidence interval [CI] 1.04 to 16.52, P = 0.044); this persisted following adjustment for prespecified patient characteristics (all RR ≥ 3.76, all P ≤ 0.060). One-year mortality post-MARS initiation was high overall but highest among the CKRT group (59% [17/29] vs. 25% [5/20] unadjusted RR 2.92, 95% CI 1.08 to 7.94, P = 0.035). Liver transplant after MARS occurred in 41% of patients (20/49). After CKRT, 39% of patients (9/29) recovered kidney function prior to hospital discharge. Conclusions: Patients requiring MARS frequently have AKI warranting the use of concomitant CKRT, which is associated with a high rate of in-hospital and 1-year mortality.

Artificial Liver Support with CytoSorb and MARS in Liver Failure: A Retrospective Propensity Matched Analysis.

BACKGROUND: Liver failure represents a life-threatening organ dysfunction with liver transplantation as the only proven curable therapy to date. Liver assist devices have been extensively researched to either bridge such patients to transplantation or promote spontaneous recovery. The aim of our study was to compare two such devices, the Molecular Adsorbent Recirculating System (MARS) and CytoSorb, in patients with liver failure. METHODS: We retrospectively included 15 patients who underwent MARS during their intensive care unit stay and matched them to 15 patients who underwent hemoadsorption using CytoSorb. Clinical and paraclinical data obtained after each individual session, after the course of treatment, as well as at the end of the intensive care unit stay were compared between the two groups. RESULTS: Single sessions of CytoSorb and MARS were both associated with a significant decrease in bilirubin (p = 0.04 and p = 0.04, respectively) and ammonia levels (p = 0.04 and p = 0.04, respectively), but only CytoSorb therapy was associated with a decrease in lactate dehydrogenase levels (p = 0.04) and in platelet count (p = 0.04). After the course of treatment, only CytoSorb was associated with a significant decrease in lactate (p = 0.01), bilirubin (p = 0.01), ammonia (p = 0.02), and lactate dehydrogenase levels (p = 0.01), while patients treated with MARS did not show any improvement in paraclinical liver tests. In addition, only CytoSorb treatment was associated with a significant improvement in the Model for End-Stage Liver Disease Score (p = 0.04). CONCLUSION: In conclusion, our results show a potential benefit of CytoSorb in rebalancing liver functional tests in patients with liver failure compared to MARS but the exact effects on patient outcome, including hospital length of stay and survival, should be further investigated in randomized control trials.

The Efficacy of Albumin Dialysis in the Treatment of Severe Cholestatic Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a significant cause of acute liver injury and can present as cholestatic injury with or without associated hepatitis. Although most patients with DILI recover with supportive care, some can develop severe refractory cholestasis that impairs recovery of hepatic function, with subsequent progression to acute or chronic liver failure. Current pharmacotherapy and extracorporeal therapies such as hemodialysis have limited benefit. Albumin dialysis is an emerging strategy in the extracorporeal treatment of intoxications caused by protein bound drugs and can be used for the removal of albumin bound bilirubin and bile acids. CASES SERIES: We describe the efficacy of albumin dialysis with the molecular adsorbent recirculating system (MARS) in the successful treatment of five patients with severe cholestatic DILI that was refractory to standard medical therapy. All patients had a sustained improvement in serum bilirubin levels after completing MARS therapy, with a complete resolution of their liver injury. DISCUSSION: Our case series demonstrates that albumin dialysis could provide an important treatment strategy in the setting of severe refractory cholestatic DILI and be considered as a novel therapeutic option in specific cases of drug hepatotoxicity in which the causative agent has high protein binding characteristics.

Artificial liver support in patients with liver failure: a modified DELPHI consensus of international experts.

The present narrative review on albumin dialysis provides evidence-based and expert opinion guidelines for clinicians caring for adult patients with different types of liver failure. The review was prepared by an expert panel of 13 members with liver and ntensive care expertise in extracorporeal liver support therapies for the management of patients with liver failure. The coordinating committee developed the questions according to their importance in the management of patients with liver failure. For each indication, experts conducted a comprehensive review of the literature aiming to identify the best available evidence and assessed the quality of evidence based on the literature and their experience. Summary statements and expert's recommendations covered all indications of albumin dialysis therapy in patients with liver failure, timing and intensity of treatment, efficacy, technical issues related to the device and safety. The panel supports the data from the literature that albumin dialysis showed a beneficial effect on hepatic encephalopathy, refractory pruritus, renal function, reduction of cholestasis and jaundice. However, the trials lacked to show a clear beneficial effect on overall survival. A short-term survival benefit at 15 and 21 days respectively in acute and acute-on-chronic liver failure has been reported in recent studies. The technique should be limited to patients with a transplant project, to centers experienced in the management of advanced liver disease. The use of extracorporeal albumin dialysis could be beneficial in selected patients with advanced liver diseases listed for transplant or with a transplant project. Waiting future large randomized controlled trials, this panel experts' statements may help careful patient selection and better treatment modalities.

Molecular adsorbent recirculating system (MARS) and continuous veno-venous hemodiafiltration (CVVHDF) for diltiazem removal: An in vitro study.

The objective of the present study was to evaluate the efficacy of the molecular adsorbent recirculating system (MARS) vs continuous veno-venous hemodiafiltration (CVVHDF). Diltiazem poisoning was simulated in a central compartment consisting in a 5L dialysis solute spiked with diltiazem at two different toxic concentrations: 750 and 5000 µg/L. For CVVHDF, mean extraction coefficients (EC = (in concentration - out concentration)/in concentration) were concentration-dependent with a decrease all along the dialysis. At the end of the sessions the mean amounts remaining in the central compartment were 8% and 7% of the initial dose at 750 and 5000 µg/L, respectively. The mean cumulative amounts found in the effluent were 60% and 75% of the initial dose, respectively. The missing amounts accounted for 32% and 18% of the initial dose, respectively, corresponding to an adsorption to the dialysis membrane. In contrast, the different compartments of the MARS resulted in undetectable output concentration earlier that the end of the session. The mean concentrations of diltiazem remaining in the central compartment were <1 µg/L at the end of the sessions. Global ECs were around 50% all along the experiment at both concentrations, and the average charcoal cartridge ECs was 80% throughout the experiments.CVVHDF system in the developed model was efficient for diltiazem removal, mainly by diffusion, convection and to a lesser extent by adsorption to the dialysis membrane. In MARS system, resin cartridge and hemodialysis components are ineffective, charcoal cartridge is responsible for almost all drug removal.

MARS: Should I Use It?

Severe liver failure, including acute liver failure and acute-on-chronic liver failure, is associated with high mortality, and many patients die despite aggressive medical therapy. While liver transplantation is a viable treatment option for liver failure patients, a large proportion of these patients die given the shortage in the liver donation and the severity of illness, leading to death while waiting for a liver transplant. Extracorporeal liver support devices, including molecular adsorbent recirculating system (MARS), have been developed as bridge to transplantation (bridge for patients who are decompensating while waiting for liver transplantation) and bridge to recovery (for whom recovery is deemed reasonable). In addition to its uses in acute liver failure and acute-on-chronic liver failure, the MARS system has also been applied in various clinical settings, such as drug overdosing and poisoning and intractable cholestatic pruritus refractory to pharmacological treatment. This review aims to discuss the controversies, potential benefits, practicalities, and disadvantages of using MARS in clinical practice.

Molecular Adsorbent Recirculating System Therapy with Continuous Renal Replacement Therapy Enhanced Clearance of Piperacillin in a Pediatric Patient and Led to Failure to Attain Pharmacodynamic Targets.

Molecular adsorbent recirculating system (MARS), an extracorporeal support device used in patients with liver failure, specifically removes albumin-bound molecules, including antibiotics. Case reports in adult patients showed that MARS enhances the clearance of piperacillin. However, for those patients, pharmacodynamic targets were achieved when piperacillin/tazobactam was administered as extended infusions over 3-4 hours. In contrast, piperacillin/tazobactam is typically given as short intermittent infusions in children. No reports describe the effect of MARS on piperacillin pharmacokinetics or pharmacodynamic target attainment in pediatric patients with liver failure. This case report describes the effects of MARS on piperacillin clearance and target attainment in a child with liver failure. It was noted that MARS, in conjunction with continuous renal replacement therapy (CRRT), enhanced the clearance of piperacillin when compared with CRRT alone (6.4-7.4 L/hr vs 3.0 L/hr). Pharmacodynamic targets were not attained during MARS-CRRT cycles with free piperacillin concentrations being above 64 µg/ml for < 50% of dosing intervals, the goal target. We performed simulation analysis to identify a dosing regimen to optimize target attainment. For this patient, doses 3 times what she received over 3-hour extended infusions and an additional dose within 5 hours of cycle initiation would have led to target attainment throughout the MARS-CRRT cycles.

Extracorporeal Elimination of Piperacillin/Tazobactam during Molecular Adsorbent Recirculating System Therapy.

Use of the Molecular Adsorbent Recirculating System (MARS) as a liver support device continues to grow worldwide. Various components of the MARS circuit remove both protein-bound and water-soluble molecules. Little is known about the extent of the enhanced clearance mechanisms used in MARS therapy on drug elimination. Of particular interest to acute care practitioners is the impact of MARS on antibiotic clearance, as suboptimal concentrations of such drugs can negatively impact patient outcomes. The properties of piperacillin/tazobactam suggest that elimination may be enhanced in the setting of MARS therapy. We describe two cases in which this was studied. Piperacillin concentrations were determined at various points within the MARS circuit, and patient serum concentrations were reported throughout the dosing interval while receiving MARS therapy. Piperacillin concentrations in both cases were in excess of the desired goal minimum inhibitory concentrations for treatment of gram-negative infections. Use of an extended-infusion strategy of piperacillin/tazobactam 3.375 or 4.5 g given every 8 hours maintained desired serum levels throughout the dosing interval. To our knowledge, this is the second published report on the use of piperacillin/tazobactam during MARS therapy. These case reports reveal successful dosing strategies for patients requiring piperacillin/tazobactam while receiving MARS therapy, as well as quantify the influence of individual MARS elements on drug extraction.

Mixed amlodipine/valsartan overdose treated by the molecular adsorbent recirculating system (MARS™).

CASE REPORT: We describe the case of a 58-year-old woman who developed a severe distributive shock following the intentional ingestion of a large overdose of amlodipine (480 mg) combined with valsartan (3680 mg). Extreme vasoplegia remained refractory to maximal standard therapy including fluid resuscitation, intravenous calcium, vasopressors at very high doses, hyperinsulinemia-euglycemia therapy, lipid emulsion, and methylene blue administration. Besides, the patient exhibited hyperglycemia refractory to very high doses of insulin. Due to its theoretical ability to effectively remove protein-bound drugs such as amlodipine from the circulation, albumin dialysis with the molecular adsorbent recirculating system (MARS™) was performed during two consecutive sessions. Blood was drawn for toxicokinetic calculations. Amlodipine elimination half-life during the first MARS™ session was calculated at 7.6 h. In addition, there was a rapid fall in blood glucose, requiring the introduction of a continuous infusion of glucose in order to achieve euglycemia. Moreover, a few hours after the initiation of the MARS™ therapy, the hemodynamic status was not significantly modified but a significant tapering of epinephrine infusion was possible, together with a progressive decrease of blood lactate level. However, the need for vasopressors in decreasing doses was present until day 5 post-ingestion. Eventually, the patient fully recovered and was discharged home 8 days after admission. DISCUSSION: The role of the MARS™ in the treatment of severe poisoning of calcium channel blockers is still to be defined. We were able to demonstrate a relatively short elimination half-life of amlodipine. A decreased insulin resistance and a reduction of epinephrine infusion were also observed.