V. Morabito

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.

Pediatric Acute Liver Failure With Molecular Adsorbent Recirculating System Treatment

BACKGROUND The prognosis of pediatric acute liver failure (PALF) has been significantly improved by emergency orthotopic liver transplantation (OLT). Since 2004, the molecular adsorbent recirculating system (MARS) has been proposed as a bridging procedure. The aim of our study was to assess its efficacy in children with PALF. PATIENTS AND METHODS Since 1999 we performed treatment of 39 fulminant hepatic failure (FHF) cases with MARS. Since September 2004 we treated 6 pediatric patients with FHF who were of mean age 10.6 years (range, 3-15 years) including 4 females and 2 males. In 3 cases the cause of FHF was unknown; in 2 cases, it was induced by paracetamol overdose; and in 1, by acute hepatitis B virus. Inclusion criteria were: bilirubin >15 mg/dL; creatinine >or=2 mg/dL; encephalopathy grade >II; and International normalized ratio (INR) >2.5. Other estimated parameters were: AST and ALT serum levels, lactate, and urine volume. Neurological status was monitored using the Glasgow Coma Scale (GCS). Continuous MARS treatment was performed in all patients with a kit change every 8 hours. Intensive care unit (ICU) treatment was applied to optimize regeneration and to prevent cardiovascular complications. RESULTS We observed a significant improvement among levels of bilirubin (P< .009), ammonia (P< .005), creatinine (P< .02), GCS (P< .002), and predictive criteria and as Sequential Organ Failure Assessment (SOFA) and Pediatric End-Stage Liver Disease (PELD). Three children underwent OLT: 1 died after 5 days due to primary nonfunction and 2 children are alive after a median follow-up of 14 months. In 2 children the MARS treatment led to resolution of clinical status without liver transplantation. One child died before OLT due to sepsis and multiorgan failure. CONCLUSIONS We concluded that application of the MARS liver support device in combination with experienced ICU management contributed to improve the clinical status in children with PALF awaiting liver transplantation.

Cytokine Level Modifications: Molecular Adsorbent Recirculating System Versus Standard Medical Therapy

INTRODUCTION Acute-on-chronic liver failure (ACLF) is a systemic inflammatory reaction, which is characterized by a predominantly proinflammatory cytokine profile, causing the transition from stable cirrhosis to ACLF. The aim of the present study was to evaluate the changes in several cytokines associated with inflammatory liver disease and liver regeneration among 15 ACLF patients treated with the Molecular Adsorbent Recirculating System (MARS) compared with 15 patients treated with standard medical therapy (SMT). The subjects showed various disease etiologies but similar values for Model End-stage Liver Disease scores. METHODS In the MARS group, 15 (10 male and 5 female) patients were treated with MARS (Gambro). The number of MARS applications was nine; the length of applications was 8 hours. In the SMT group; 15 (10 male and 5 female) patients were treated with SMT. The patients were monitored for 30 days from inclusion with a survival follow-up at 3 months. Statistical results were calculated with SPSS14.0 (SPSS Inc, Chicago, Ill). A P < .07 was considered significant. RESULTS In the MARS group, we observed significant changes in the levels of Interleukin (IL)-6, IL-1, IL-10, and tumor necrosis factor (TNF)-alpha in association with improved hepatocyte growth factor. Patient survival at 3 months was 60%. The SMT group showed only a significant change in TNF-alpha (P = .03). Patient survival at 3 months was 30%. CONCLUSION The MARS liver support device corrected pathophysiologies of ALF and may be used to enhance spontaneous recovery or as a bridge to transplantation.

Clinical Results of Treatment of Postsurgical Endotoxin-Mediated Sepsis With Polymyxin-B Direct Hemoperfusion

We evaluated the possibility of preventing the evolution of endotoxin-mediated sepsis in severe septic shock using early treatment of critical endotoxemia with polymyxin-B direct hemoperfusion (PMX-DHP). Thirty-eight postsurgical patients who fulfilled at least 2 criteria for systemic inflammatory response syndrome were stratified on the basis of the value of the endotoxin activity assay. Seventeen patients who demonstrated high risk of endotoxin activity (>or=0.6) received standard therapy plus PMX-DHP every 24 hours to lower the endotoxin activity level to less than 0.4, and the remaining 21 patients with endotoxin activity levels less than 0.6 received standard therapy only. Seven patients required 2 courses of PMX-DHP therapy, 8 required 3 courses, and 2 required 4 courses. After treatment, mean arterial pressure increased, from 69.00 mm Hg to 81.35 mm Hg (P < .01); heart rate decreased, from 105.40 bpm to 78.12 bpm (P < .01); white blood cell count decreased, from 20,700 cells/mm(3) to 9740 cells/mm(3) (P < .01); arterial oxygen tension-fraction of inspired oxygen ratio increased, from 273.82 to 305.82 (P < .01); and Sequential Organ Failure Assessment score decreased, from 7 to 4 (P < .01). Length of stay was longer for transplant recipients (16 days) than for other surgical patients (8(1/2) days). All patients survived to 28-day follow-up, and 15 of 16 patients (94%) had survived at 60-day follow-up. Despite the small number of patients included in the study, the encouraging results suggest that PMX-DHP is a useful therapeutic strategy for lowering sepsis-related mortality.

Pathfast presepsin assay for early diagnosis of bacterial infections in surgical patients: preliminary study.

BACKGROUND Various biomarkers have been studied for diagnosing bacterial infections, seeking to stop the sepsis cascade. Presepsin, which is ∼13 kDa in size, has been identified to increase specifically in the blood of sepsis patients. Additionally, measurement of presepsin is useful to evaluate the severity of infection and monitor clinical responses. We evaluated the analytical and clinical performance of the Pathfast presepsin (PFP) assay system for early diagnosis of infection. MATERIALS AND METHODS From November 2011 to June 2012 we studied 70 adult patients, including 35 cadaveric organ transplant recipients and 35 abdominal surgery patients. The 32 female and 38 male subjects had a mean age of 56.1 years (range, 19-70). Heparinized whole blood for PFP assay was tested at 48 hours after surgery together with blood cultures. RESULTS The mean presepsin level (PL) in the 50 positive patients was 3,957.45 pg/mL (range 255-20,000). For transplant patients, PL was 3,034.43 ± 2,880.791 pg/mL, with 30 positive results. Microbiologic findings confirmed the presence of bacterial infections within 69 ± 2.5 hours from enrollment despite that when the test was performed, 70% showed no sign or symptom of infection. In 15 abdominal surgery patients, the PFP test was negative with negative blood cultures. The positive PFP test in 20 other abdominal surgery patients showed PL of 2,363 ± 7,988.47 pg/mL in the absence of signs or symptoms of infection in 25% of them. The 20 positive patients showed positive blood cultures within 67 ± 1.8 hours from enrollment. CONCLUSIONS The PFP test had a (100%) sensitivity to show the presence of infection in a short time (15 min), confirmed by positive blood cultures.

Predictive Parameters After Molecular Absorbent Recirculating System Treatment Integrated With Model for End Stage Liver Disease Model in Patients With Acute-on-Chronic Liver Failure

AIM The aim of study was to highlight parameters that in association with Model for End-stage Liver Disease (MELD) provide predictive criteria for long-term survival after treatment with the Molecular Adsorbent Recirculating System (MARS). Two homogenous groups were studied: one treated with standard medical therapy (SMT) and the other, with MARS. MATERIALS AND METHODS Twenty acute-on-chronic liver failure patients on the waiting list for liver transplantation and affected by alcoholic cirrhosis with similar MELD scores (20-29) were evaluated for 7 days from inclusion and for 6-month survival. Ten patients (seven males and three females) were treated with MARS. Their mean age was 48.5 years (range = 35-61). The number of MARS applications was six for 6 consecutive days, and the length of the applications was 8 hours. Ten other patients (seven males and three females) were treated with SMT, including prophylaxis against bacterial infections and judicious use of diuretics. The precipitating factors were also treated appropriately. The mean age of the patients was 51 years (range = 37-64). All the variables that were significant upon univariate analysis were enrolled in a receiver operating characteristic analysis, with the intention to detect predictive parameters for patient death at 6 months. We considered a significant area under curve (AUC) value to be greater than 0.5. RESULTS Among 11 patients who died within 6 months there were in the MARS group and eight in the SMT group: the 3- and 6-month patient survival rates were 90% and 70% versus 30% and 20% in the two groups, respectively. Nine measures resulted in an AUC > 0.5: DeltaMELD; interleukin (IL)-8; IL-6; tumor necrosis factor- alpha, MELD score; creatinine, bilirubin international normalized ratio (INR) and cardiac index. DeltaMELD and postoperative IL-8 concentrations showed better results (AUC = 0.899), followed by postoperative creatinine (AUC = 0.879), postoperative cardiac index (AUC = 0.833), and postoperative INR (AUC = 0.818). Postoperative creatinine showed the best sensitivity (100%), while IL-8, the best specificity (88.9%). CONCLUSION A combination of biochemical and clinical variables probably represent the best way to predict the survival of patients, allowing physicians to select the best therapies for each patient.

Preoperative donor scores and postoperative early measures of graft function: relevance to the outcome of liver transplantation.

BACKGROUND Several donor and recipient parameters play a role in the determination of post-liver transplant allograft function. The identification of prognostic indices presents great implications for correct allocation of donors and more targeted recipient management. The aim of our review was to detect the role of preoperative scoring systems and early postoperative measures of graft function as predictive factors for the development of graft failure and recipient death. METHODS We stratified a cohort of 97 patients in two groups according to a 1-year functional (Group A; n = 72) versus non-functional (Group B; n = 25) status of the allograft. RESULTS Patients in group B showed higher preoperative Model for End-stage Liver Disease (MELD) values, longer warm ischemia times, reduced bile outputs and increased peak values of transaminases and INR content within the first 3 days after transplantation. Group B showed 48% of patients with initial poor graft function. The parameters which resulted in a significant prediction of graft loss by multivariate analysis were MELD (P = .012); postoperative day 1 serum alanine aminotransferase (ALT) (P < .0001) and day 3 ALT (P = .003). The predictive factors for patient death were postoperative day 1 serum ALT (P < .0001) and day 3 ALT (P = .001). CONCLUSIONS MELD score was a useful preoperative parameter for the prediction of post-transplant graft survival. Early ALT values predicted both graft and recipient survivals. Minimization of parameters related to their peaks (warm ischemia time) may improve graft and patients survival rates.

Management of Sepsis During MARS Treatment in Acute on Chronic Liver Failure

INTRODUCTION The aim of our study was a 30-day follow-up of the use of early detection of endotoxin by the endotoxin activity assay (EAA) for patients with acute liver failure superimposed on chronic liver disease (AoCLF) and treated with polymyxin-B hemoperfusion-based (PMX-DHP) treatment and albumin dialysis in the molecular adsorbent recirculating system (MARS). MATERIALS AND METHODS From February 2008 to July 2010, we evaluated 10 AoCLF patients experiencing systemic inflammatory response syndrome (SIRS) in association with suspected infection and an EAA-positive test (>0.60). These patients awaiting liver transplantation (OLT) showed similar Model End-Stage Liver Disease (MELD) scores (range, 19-25) and encephalopathy grade ≤ 2. Five patients received therapy to remove endotoxins with PMX-DHP with MARS treatment for liver failure (group A); the other 5 patients received MARS treatment only (group B). RESULTS Two PMX-DHP treatments were performed in 4 group A patients (average EA=0.66 [range, 0.61-0.70]) and 3 treatments for 1 patient (EA=0.92). All 5 subjects underwent an average of 4 MARS treatments (range, 3-5). At the end of therapy, the median EA level was 0.42 (range, 0.37-0.48). As reported in the literature, we achieved a significant improvement in liver and kidney functions using MARS. Measurements of lactate, interleukin (IL)-6, and tumor necrosis factor (TNF)-α were significantly improved among patients treated with the extracorporeal therapies. At 30 days of observation, all 5 patients treated with MARS plus PMX-DHP are alive. In group B, a mean of 7.5 MRAS treatments were performed. We observed an improvement in hemodynamic and liver functions with reduced levels of proinflammatory cytokines and lactates in 4 patients. One patient showed no improvement in clinical status with the development of sepsis and subsequent multiorgan failure after 24 days. CONCLUSION The possibility of an early diagnosis using the EAA in AoCLF patients could prevent the progression of the sepsis cascade. The use of PMX-DHP and MARS in these patients, could lead to resolution of clinical status in a short time.

Hemodynamic Improvement as an Additional Parameter to Evaluate the Safety and Tolerability of the Molecular Adsorbent Recirculating System in Liver Failure Patients

BACKGROUND The molecular adsorbent recirculating system (MARS) is an extracorporeal acute liver failure (ALF) support system method using albumin-enriched dialysate to remove albumin-bound toxins. PATIENTS AND METHODS Since 1999 we performed 2027 MARS treatments in 191 patients: 39 fulminant hepatic failure (FHF), 16 primary nonfunction (PNF), 21 delayed function (DF), 94 acute-on-chronic liver failure (AoCHF), 7 post-hepatic resection, and 14 intractable pruritus. RESULTS We divided the complications by the AoCHF versus the ALF populations. Among 83 ALF patients, we observed worsening of hemodynamic parameters in 16 patients: 3 with PNF, 2 with DF without retransplantation, 9 with FHF, and 2 after hepatic resection. Among 94 AoCHF patients, 42 showed hemodynamic instability requiring intensive care unit support. Our study did not note significant adverse effects (1.8%), except for infections and hemorrhage from the central venous catheter not due to MARS treatment. The thrombocytopenia was controlled through administration of platelets before the start of treatment when a patient showed a level under 30,000 mm(3). CONCLUSION Our results confirmed that nonbiological hepatic support by MARS was safe and tolerable.

Primary Nonfunction: Timing Retransplantation Versus Hemodynamic Parameters and Kidney Function

BACKGROUND Patients with acute liver failure (ALF) show an aggravated hyperdynamic circulation. We evaluated potential changes in systemic hemodynamics and improved kidney function induced by the molecular adsorbent recirculating system (MARS) in a group of patients with primary nonfunction (PNF). PATIENTS AND METHODS In the intensive care unit we treated 18 patients with PNF (6 females and 12 males) after orthotopic liver transplantation (OLT) of overall mean age 47.8 years (range, 28-60 years). Continuous MARS treatment was performed on all patients with a kit change every 8 hours during a mean of 10 days (range, 1-20 days). Double-lumen catheter type veno-venous access was used for the blood supply. The blood flow rate was 150 to 250 mL/min, depending on the hemodynamic situation of the patient. Blood passed through an albumin nonpermeable, high flux dialysis membrane. During MARS treatment we monitored the hemodynamic condition, using a series of parameters: heart rate (HR), mean arterial pressure (MAP), cardiac index (CI), systemic vascular resistance index (SVRI), and pulmonary vascular resistance index (PVRI) before (baseline value) as well as after 1 hour (T1), 3 hours (T2), and the end of treatment (T3). RESULTS There was a progressive decrease in positive inotropic support (dobutamine, norepinephrine) and significant improvement in hemodynamic parameters, such as MAP (P< .01), PVRI/SVRI/V(mean) (P< .002), and KARI (P< .01). The improved kidney functions were shown by significant improvements in serum creatinine (P< .03), urea (P< .02), and urine volume (P< .005). Eleven patients were alive: 6 with OLT and 5 without OLT. Seven patients died: 4 after OLT and 3 before OLT due to multiorgan failure. CONCLUSIONS The MARS device significantly improved the hemodynamic parameters and kidney function that also determine patient survival in ALF (61.1%) with PNF while awaiting retransplantation presumably by removal of certain vasoactive substances.