Hubert Hetz

Heightened levels of circulating 20S proteasome in critically ill patients

Background  Recently, circulating proteasome core particles (20S proteasome) have been suggested as a marker of cell damage and immunological activity in autoimmune diseases. Aberrant leucocyte activation and increased lymphocyte apoptosis with consecutive T‐cell unresponsiveness is deemed to play a pivotal role in the sepsis syndrome. Moreover sepsis‐induced muscle proteolysis mainly reflects ubiqutin proteasome‐dependent protein degradation. We therefore sought to investigate serum levels of 20S proteasome in critical ill patients.

Molecular adsorbent recirculating system and hemostasis in patients at high risk of bleeding: an observational study

IntroductionLiver failure is associated with reduced synthesis of clotting factors, consumptive coagulopathy, and platelet dysfunction. The aim of the study was to evaluate the effects of liver support using a molecular adsorbent recirculating system (MARS) on the coagulation system in patients at high risk of bleeding.MethodsWe studied 61 MARS treatments in 33 patients with acute liver failure (n = 15), acute-on-chronic liver failure (n = 8), sepsis (n = 5), liver graft dysfunction (n = 3), and cholestasis (n = 2). Standard coagulation tests, standard thromboelastography (TEG), and heparinase-modified and abciximab-fab-modified TEG were performed immediately before and 30 minutes after commencement of MARS, and after the end of MARS treatment. Prostaglandin I2 was administered extracorporeally to all patients; 17 patients additionally received unfractioned heparin.ResultsThree moderate bleeding complications in three patients, requiring three to four units of packed red blood cells, were observed. All were sufficiently managed without interrupting MARS treatment. Although there was a significant decrease in platelet counts (median, 9 G/l; range, -40 to 145 G/l) and fibrinogen concentration (median, 15 mg/dl; range, -119 to 185 mg/dl) with a consecutive increase in thrombin time, the platelet function, as assessed by abciximab-fab-modified TEG, remained stable. MARS did not enhance fibrinolysis.ConclusionMARS treatment appears to be well tolerated during marked coagulopathy due to liver failure. Although MARS leads to a further decrease in platelet count and fibrinogen concentration, platelet function, measured as the contribution of the platelets to the clot firmness in TEG, remains stable. According to TEG-based results, MARS does not enhance fibrinolysis.

Regional citrate anticoagulation in patients with liver failure supported by a molecular adsorbent recirculating system.

Objective:Regional citrate anticoagulation has emerged as a promising method in critically ill patients at high risk of bleeding. However, in patients with liver failure, citrate accumulation may lead to acid-base and electrolyte imbalances, notably of calcium. The aim of this study was to evaluate the feasibility and safety of regional citrate anticoagulation during liver support using a molecular adsorbent recirculating system as well as its effects on electrolyte and acid-base balance in patients with liver failure. Design:Prospective observational study. Setting:University hospital. Patients:Twenty critically ill patients supported by molecular adsorbent recirculating system resulting from liver failure between January 2007 and May 2009. Measurements and Main Results:The median duration of molecular adsorbent recirculating system treatment was 20 hrs (interquartile range, 18−22 hrs). Two of 77 molecular adsorbent recirculating system treatments (2%) were prematurely discontinued as a result of filter clotting and bleeding, respectively. The median citrate infusion rate, necessary to maintain the postfilter ionized calcium between 0.2 and 0.4 mmol/L, was 3.1 mmol/L (interquartile range, 2.3–4 mmol/L) blood flow. The median calcium chloride substitution rate was 0.9 mmol/L (0.3–1.7 mmol/L) dialysate. Total serum calcium remained stable during molecular adsorbent recirculating system treatments. There was a statistically significant increase of the ratio of total calcium to systemic ionized calcium (2.04 ± 0.32 mmol/L to 2.17 ± 0.35; p = .01), which reflected citrate accumulation resulting from liver failure. Under close monitoring, no clinically relevant electrolytes or acid-base disorders were observed. Conclusions:Our results suggest that regional citrate anticoagulation is a safe and feasible method to maintain adequate circuit lifespan without increasing the risk of hemorrhagic complications while maintaining a normal acid-base as well as electrolyte balance in patients with liver failure supported by molecular adsorbent recirculating system.

Transesophageal echocardiography during orthotopic liver transplantation in patients with esophagoastric varices.

Background Hemodynamic monitoring using transesophageal echocardiography (TEE) in patients with signs of portal hypertension undergoing orthotopic liver transplantation (OLT) carries potential risk of esophageal and gastric variceal hemorrhage. The aim of our retrospective analysis was to evaluate the safety of intraoperative TEE monitoring during OLT in patients with esophagogastric varices. Methods A retrospective analysis of 396 liver transplant recipients was performed at the Medical University of Vienna monitored by TEE during OLT between 2003 and 2010. Results Varices were documented by esophagogastroduodenoscopy in 287 (72.5%) of 396 analyzed patients: 130 (32.8%) varices grade I (<5 mm under insufflation) and 157 (39.6%) varices grade II (>5 mm under insufflation). Red spot signs were identified in 40 patients (10.1%). Most varices (82.2%) were documented in the esophagus, 4.2% in the stomach, and 13.6% in both (esophagus and stomach). Only one major bleeding occurred, and it was only in a case of one patient with an esophageal varix, which was treated with a balloon tamponade during OLT. Although patients with varices demonstrated a significantly longer prothrombin time and lower platelet count, there was no significant difference in the requirement for blood products among patients with and without varices. Conclusions TEE is a relatively safe method for monitoring cardiac performance with a low incidence of major hemorrhagic complications in patients with documented esophagogastric varices undergoing OLT.

Molecular adsorbent recirculating system in patients with early allograft dysfunction after liver transplantation: A pilot study

Early allograft dysfunction (EAD) after orthotopic liver transplantation (OLT) causes marked morbidity and mortality. We conducted a prospective pilot study to assess the safety and efficacy of molecular adsorbent recirculating system (MARS) in treatment of EAD after OLT. Twelve consecutive adult liver allograft recipients with a median age of 48 years, 9 of whom were male, were prospectively included and supported with MARS. EAD was defined as the presence of at least 2 of the following: serum bilirubin >10 mg/dL, prothrombin time <40%, aspartate aminotransferase or alanine transferase >1,000 U/L, and plasma disappearance rate of indocyanine green (PDRICG) <10% per minute within 72 hours after reperfusion. One‐year patient and graft survival was 66%. There was a significant decrease in serum bilirubin (P = 0.002), serum creatinine (P = 0.006), and aspartate aminotransferase (P = 0.005) and a significant increase in PDRICG (P = 0.007) after MARS treatment. Prothrombin time, albumin level, and platelet count remained stable. Sustained improvement of renal and neurological function and of mean arterial pressure were observed. No MARS‐related adverse effects occurred. MARS treatment provides a safe approach to the treatment of EAD after OLT. On the basis of this pilot study, a multicenter randomized clinical trial that uses MARS treatment in EAD after OLT has been initiated. Liver Transpl 12:1357‐1364, 2006.

HSP27 and HSP70 serum and urine levels in patients suffering from chronic kidney disease.

BACKGROUND Chronic kidney disease (CKD) is a condition associated with inflammation and high levels of uremic toxins and reactive oxygen species. As a counterregulation to systemic stress heat shock proteins (HSP) are increased expressed to minimize cell death and preserve cell integrity by inhibiting apoptotic pathways. The aim of this study was to determine HSP27 and HSP70 concentrations in sera and urine of patients suffering from CKD. METHODS Concentrations of HSP27 and HSP70 in urine and serum were determined in 119 patients with CKD stages 1 to 5 and 23 healthy volunteers by using ELISA technique. RESULTS HSP27 serum levels were significantly elevated in patients suffering from CKD stages 3 to 5 as well as fractional HSP27 excretion in stages 2-5 versus healthy controls. Absolute HSP70 urinary values were significantly elevated in stages 4 and 5 and fractional HSP70 excretion was increased in stage 5 compared to controls. Moreover, ROC curve analysis showed the potential of urine and especially serum HSP levels to identify various stages of CKD. CONCLUSION We provide evidence for elevated HSP27 concentrations in serum and urine and increased HSP70 excretion levels in patients suffering from CKD. Moreover, our results show that HSP levels might offer potential to examine the stages of CKD as well as the disease course which could further promote individually adjusted treatment planning.

Dynamic changes in MELD score not only predict survival on the waiting list but also overall survival after liver transplantation

The predictive value of MELD score for post‐transplant survival has been under constant debate since its implementation in 2001. Aim of this study was to assess the impact of alterations in MELD score throughout waiting time (WT) on post‐transplant survival. A single‐centre retrospective analysis of 1125 consecutive patients listed for liver transplantation between 1997 and 2009 was performed. The impact of MELD score and dynamic changes in MELD score (DeltaMELD), as well as age, sex, year of listing and WT were evaluated on waiting list mortality and post‐transplant survival. In this cohort, 539 (60%) patients were transplanted, 223 (25%) died on list and 142 (15%) were removed from the waiting list during WT. One‐, three‐ and five‐year survival after liver transplantation were 83%, 78% and 76% respectively. DeltaMELD as a continuous variable proved to be the only significant risk factor for overall survival after liver transplantation (hazard ratio (HR): 1.06, 95% confidence interval (CI) 1.02–1.1, P = 0.013). The highest risk of post‐transplant death could be defined for patients with a DeltaMELD > 10 (HR: 4.87, 95% CI 2.09–11.35, P < 0.0001). In addition, DeltaMELD as well as MELD at listing showed a significant impact on waiting list mortality. DeltaMELD may provide an easy evaluation tool to identify patients on the liver transplant waiting list with a high mortality risk after transplantation in the current setting. Temporarily withholding and re‐evaluating these patients might improve overall outcome after liver transplantation.

Short-term versus long-term induction therapy with antithymocyte globulin in orthotopic liver transplantation.

T‐cell depletion is an essential aspect of clinical immunosuppression. The aim of the present study was to compare the efficacy of two dosage regimens in this setting. We retrospectively compared 246 patients (group 1) who received a 10‐day antithymocyte globulin (ATG) induction protocol with 226 patients (group 2) who received a 3‐day protocol. The 6‐month rejection rate was 22.3% in group 1 and 12.7% in group 2 (P = 0.03). The sub‐analysis showed a higher rejection rate in patients with cholestatic disease (P = 0.01), who were more numerous in group 1. This resulted in an overall difference between the groups. Rates of de novo malignancies and recurrent hepatocellular carcinoma were identical. Viral infection rates were 16% and 18%, respectively (P > 0.5). The rates of bacterial and fungal infection were also similar (37% vs. 42%, P > 0.1). However, infection and ATG administration are independent risk factors for survival. A lower rate of fatal infection was observed in group 2 (P = 0.01), while the 10‐day ATG regimen had a detrimental effect on patients who had infection (P < 0.0001). Our results strongly support the application of 3‐day ATG induction therapy regimen after orthotopic liver transplantation, as it is associated with the same rejection rate as long‐term ATG induction therapy, without the negative survival effect of the latter due to lethal infection.

MCP-1 and MIP3-alpha serum levels in acute liver failure and molecular adsorbent recirculating system (MARS) treatment: A pilot study

Objective. The CC chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-3 alpha (MIP3-alpha) may be involved in the pathogenesis of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). In ALF and ACLF, the molecular adsorbent recirculating system (MARS) has been used to support liver function. Enhancement of MCP-1, as seen in other extracorporeal support systems such as haemodialysis, might thus have mitigated the beneficial effects of the MARS system in acute hepatic failure. Material and methods. Serum concentrations of MCP-1 and MIP3-alpha were measured in 10 patients with ALF or ACLF treated with MARS. Thirteen patients suffering from chronic hepatic failure (CHF) and 15 healthy individuals served as controls. Results. Baseline MCP-1 serum concentrations were significantly increased in ALF and ACLF patients as compared to patients with CHF (p=0.0027 and p=0.0046, respectively) and controls (p=0.0006 and p=0.0012, respectively). MIP3-alpha serum concentrations were also significantly enhanced in the ALF and ACLF groups as compared with those in CHF patients (p=0.0002 and p=0.0003, respectively) and controls (p<0.0001 and p<0.0001, respectively). Moreover, MIP3-alpha levels were significantly increased in CHF patients as compared to controls (p=0.0002). MCP-1 and MIP3-alpha concentrations did not change significantly during MARS treatment in ALF and ACLF patients. Conclusions. The CC chemokines MCP-1 and MIP3-alpha are increased in ALF and ACLF patients. MARS had no effect on MCP-1 and MIP3-alpha serum concentrations in patients with ALF and ACLF, and yielded no evidence of any harmful effects of the increase of these potentially hepatocidal chemokines.

Pro-inflammatory Interleukin-18 and Caspase-1 serum levels in liver failure are unaffected by MARS treatment

BACKGROUND The pro-inflammatory cytokine IL-18 and its activator Caspase-1 are involved in acute liver failure and acute-on-chronic-liver-failure. In acute liver failure and acute-on-chronic-liver-failure, the MARS system has been used to support liver function. Enhancement of IL-18, as seen in other extracorporeal-support systems like hemodialysis might thus have mitigated beneficial effects of the MARS system in acute hepatic failure. PATIENTS AND METHODS We measured serum concentrations of IL-18 and Caspase-1 in 10 patients with acute liver failure and 10 patients suffering from acute-on-chronic-liver-failure, who were all treated with MARS. Thirteen patients suffering from chronic hepatic failure and 15 healthy individuals served as controls. Data are given as mean with 95% CI. RESULTS Baseline IL-18 serum concentrations were significantly increased in acute liver failure and acute-on-chronic-liver-failure patients as compared to chronic hepatic failure (P=0.0039 and P=0.0011, respectively) and controls (P=0.0028 and P=0.0014, respectively). Caspase-1 serum concentrations were as well significantly elevated in the acute liver failure and acute-on-chronic-liver-failure groups as compared to chronic hepatic failure patients (P=0.0039 and P=0.0232, respectively) and controls P<0.0001 and P<0.0007, respectively). IL-18 and Caspase-1 did not change significantly during MARS treatment in acute liver failure and acute-on-chronic-liver-failure patients. CONCLUSIONS MARS had no effect on IL-18 and Caspase-1 serum concentrations in acute liver failure and acute-on-chronic-liver-failure, providing no evidence of harmful effects by the increase of these potentially hepatocidal cytokines.