Carsten Hafer

Prometheus® – a new extracorporeal system for the treatment of liver failure☆

BACKGROUND/AIMS Extracorporeal detoxification systems for supportive therapy of liver failure have recently gained much interest. We herein report results from the first clinical application of Prometheus, a new liver support system in which albumin-bound substances are directly removed from blood by special adsorber. In a simultaneous step, high-flux hemodialysis is performed. We assessed safety, adsorber efficiency and clinical efficacy of the Prometheus system. METHODS Eleven patients with acute-on-chronic liver failure and accompanying renal failure were treated with Prometheus on 2 consecutive days for >4 h. RESULTS Prometheus treatment significantly improved serum levels of conjugated bilirubin, bile acids, ammonia, cholinesterase, creatinine, urea and blood pH. There were no significant changes in hemoglobin and platelet levels, whereas leucocytes increased without signs of systemic infection. No treatment-related complications except a blood pressure drop in two patients with systemic infection were noted. In one patient (Child-Pugh score: 15) Prometheus treatment could not be completed due to onset of uncontrolled bleeding 16 h after dialysis. CONCLUSIONS Prometheus is a safe supportive therapy for patients with liver failure. A significant improvement of the biochemical milieu was observed already after two treatments. Prospective controlled studies with the Prometheus system are necessary to evaluate hard clinical end-points.

Effects of Fractionated Plasma Separation and Adsorption on Survival in Patients With Acute-on-Chronic Liver Failure

BACKGROUND & AIMS Fractionated plasma separation and adsorption (FPSA) is an extracorporeal procedure that supports liver function by removing endogenous toxins that cause complications from acute-on-chronic liver failure (AOCLF). We performed a randomized trial to investigate survival of patients with AOCLF treated with FPSA. METHODS Patients with AOCLF were randomly assigned to groups given a combination of FPSA and standard medical therapy (SMT) (FPSA group, n = 77) or only SMT (SMT group, n = 68). The Prometheus liver support system was used to provide 8 to 11 rounds of FPSA (minimum of 4 hours each) for 3 weeks. Primary end points were survival probabilities at days 28 and 90, irrespective of liver transplantation. RESULTS Baseline clinical parameters and number of transplant patients were similar between study arms. Serum bilirubin level decreased significantly in the FPSA group but not in the SMT group. In an intention-to-treat analysis, the probabilities of survival on day 28 were 66% in the FPSA group and 63% in the SMT group (P = .70); on day 90, they were 47% and 38%, respectively (P = .35). Baseline factors independently associated with poor prognosis were high SOFA score, bleeding, female sex, spontaneous bacterial peritonitis, intermediate increases in serum creatinine concentration, and combination of alcoholic and viral etiology of liver disease. There were no differences between the 2 groups in the incidence of side effects. CONCLUSIONS Among all patients with AOCLF, extracorporeal liver support with FPSA does not increase the probability of survival. Further studies are needed to assess whether therapy might be beneficial in specific subsets of patients.

Circulating miR-210 Predicts Survival in Critically Ill Patients with Acute Kidney Injury

BACKGROUND AND OBJECTIVES MicroRNAs (miRNAs) are small ribonucleotides regulating gene expression. MicroRNAs are present in the blood in a remarkably stable form. We tested whether circulating miRNAs in the plasma of critically ill patients with acute kidney injury (AKI) at the inception of renal replacement therapy are deregulated and may predict survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We profiled miRNAs using RNA isolated from the plasma of patients with AKI and healthy controls. The results were validated in 77 patients with acute kidney injury, 30 age-matched healthy controls, and 18 critically ill patients with acute myocardial infarction by quantitative real-time PCR. RESULTS Circulating levels of miR-16 and miR-320 were downregulated in the plasma of kidney injury AKI patients, whereas miR-210 was upregulated compared with healthy controls (all P < 0.0001) and disease controls (miR-210 and miR-16: P < 0.0001; miR-320: P = 0.03). Cox regression (P < 0.05) and Kaplan-Meier curve analysis (P = 0.03) revealed miR-210 as an independent and powerful predictor of 28-day survival. CONCLUSIONS Circulating miRNAs are altered in patients with kidney injury AKI. MiR-210 predicts mortality in this patient cohort and may serve as a novel biomarker AKI reflecting pathophysiological changes on a cellular level.

Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic–uraemic syndrome: an analysis of the German STEC-HUS registry

BACKGROUND May 22nd marks the beginning of a Shiga-toxin-producing Escherichia coli (STEC) O104:H4 outbreak in Northern Germany. By its end on 27 July, it had claimed 53 deaths among 2987 STEC and 855 confirmed haemolytic-uraemic syndrome (HUS) cases. METHODS To describe short-term effectiveness of best supportive care (BSC), therapeutic plasma exchange (TPE) and TPE with eculizumab (TPE-Ecu) in 631 patients with suspected HUS treated in 84 hospitals in Germany, Sweden and the Netherlands using the web-based registry of the DGfN (online since 27 May). RESULTS Of 631 entries, 491 fulfilled the definition of HUS (median age 46 years; 71% females). The median (inter-quartile range) hospital stay was 22 (14-31) days. Two hundred and eighty-one (57%) patients underwent dialysis and 114 (23%) mechanical ventilation. Fifty-seven patients received BSC, 241 TPE and 193 TPE-Ecu. Treatment strategy was dependent on disease severity (laboratory signs of haemolysis, thrombocytopenia, peak creatinine level, need for dialysis, neurological symptoms, frequency of seizures) which was lower in BSC than in TPE and TPE-Ecu patients. At study endpoint (hospital discharge or death), the median creatinine was lower in BSC [1.1 mg/dL (0.9-1.3)] than in TPE [1.2 mg/dL (1.0-1.5), P < 0.05] and TPE-Ecu [1.4 mg/dL (1.0-2.2), P < 0.001], while need for dialysis was not different between BSC (0.0%, n = 0), TPE (3.7%; n = 9) and TPE-Ecu (4.7%, n = 9). Seizures were absent in BSC and rare in TPE (0.4%; n = 1) and TPE-Ecu (2.6%; n = 5) patients. Total hospital mortality in HUS patients was 4.1% (n = 20) and did not differ significantly between the TPE and TPE-Ecu groups. CONCLUSIONS Despite frequent renal impairment, advanced neurological disorders and severe respiratory failure, short-term outcome was better than expected when compared with previous reports. Within the limitations of a retrospective registry analysis, our data do not support the notion of a short-term benefit of Ecu in comparison to TPE alone in the treatment of STEC-HUS. A randomized trial comparing BSC, TPE and Ecu seems to be prudent and necessary prior to establishing new treatment guidelines for STEC-HUS.

Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients

IntroductionThe endothelial specific angiopoietin (Ang)-Tie2 ligand-receptor system has been identified as a non-redundant mediator of endothelial activation in experimental sepsis. Binding of circulating Ang-1 to the Tie2 receptor protects the vasculature from inflammation and leakage, whereas binding of Ang-2 antagonises Tie2 signalling and disrupts endothelial barrier function. Here, we examine whether circulating Ang-1 and/or Ang-2 independently predict mortality in a cohort of critically ill medical patients.MethodsCirculating vascular endothelial growth factor (VEGF), Ang-1 and Ang-2 were prospectively measured in sera from 29 healthy controls and 43 medical ICU patients by immunoradiometric assay (IRMA) and ELISA, respectively. Survival after 30 days was the primary outcome studied.ResultsMedian serum Ang-2 concentrations were increasingly higher across the following groups: healthy controls, patients without sepsis, patients with sepsis and patients with septic shock. In contrast, Ang-1 and VEGF concentrations were significantly lower in all patient groups compared with healthy controls. Ang-2 correlated with partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2), tissue hypoxia, Sequential Organ Failure Assessment (SOFA) and Physiology and Chronic Health Evaluation II (APACHE II) score. Multivariate Cox regression analyses confirmed a strong independent prognostic impact of high Ang-2 as a novel marker of 30-day survival.ConclusionsA marked imbalance of the Ang-Tie system in favour of Ang-2 is present in critically ill medical patients. Our findings highlight the independent prognostic impact of circulating Ang-2 in critical illness. Ang-2 may be used as a readily available powerful predictor of outcome and may open new perspectives to individualise treatment in the ICU.

The Hannover Dialysis Outcome study: comparison of standard versus intensified extended dialysis for treatment of patients with acute kidney injury in the intensive care unit

BACKGROUND Increasing the dose of renal replacement therapy has been shown to improve survival in critically ill patients with acute kidney injury (AKI) in several smaller European trials. However, a very recent large multicentre trial in the USA could not detect an effect of dose of renal replacement therapy on mortality. Based on those studies, it is not known whether a further increase in dialysis dose above and beyond the currently employed doses would improve survival in patients with AKI. We therefore aimed to assess mortality and renal recovery of patients with AKI receiving either standard (SED) or intensified extended dialysis (IED) therapy in the intensive care unit. METHODS A prospective randomized parallel group study was conducted in seven intensive care units of a tertiary university hospital. Pre-existing chronic kidney disease was an exclusion criterion. A total of 156 patients (570 screened) with AKI requiring renal replacement therapy were randomly assigned to receive standard dialysis [dosed to maintain plasma urea levels between 120 and 150 mg/dL (20-25 mmol/L)] or intensified dialysis [dosed to maintain plasma urea levels <90 mg/dL (<15 mmol/L)]. Outcome measures were survival at Day 14 (primary) and survival and renal recovery at Day 28 (secondary) after initiation of renal replacement therapy. RESULTS Treatment intensity differed significantly (P < 0.01 for plasma urea and administered dose). No differences between intensified and standard treatment were seen for survival by Day 14 (70.4% versus 70.7%) or Day 28 (55.6% versus 61.3%), or for renal recovery amongst the survivors by Day 28 (60.0% versus 63.0%). CONCLUSIONS Although this study cannot deliver a definitive answer, it suggests that increasing the dose of extended dialysis above the currently recommended dose might neither reduce mortality nor improve renal recovery in critically ill patients, mainly septic patients, with AKI.

Serum neutrophil gelatinase-associated lipocalin at inception of renal replacement therapy predicts survival in critically ill patients with acute kidney injury

IntroductionNeutrophil gelatinase-associated lipocalin (NGAL) is a promising novel biomarker that correlates with the severity and outcome of acute kidney injury (AKI). However, its prognostic utility during the late course of AKI, especially in patients that require renal replacement therapy (RRT) remains unknown. The aim of this study was to evaluate the predictive value of serum NGAL in patients with established AKI at inception of RRT in the intensive care unit (ICU).MethodsSerum NGAL (ELISA methodology) was measured in 109 critically ill patients with AKI at inception of RRT in 7 ICUs of a tertiary care university hospital. The primary outcome studied was 28-day mortality. Secondary outcome measures were ICU length of stay, ventilator-free days, and renal recovery at day 28.ResultsThere was a significant difference in serum NGAL between healthy subjects (median [interquartile range] 39.0 [37.5-42.75] ng/mL), critically ill patients with systemic inflammatory response syndrome (SIRS) (297 [184-490] ng/mL), and critically ill patients with sepsis (708 [365-1301] ng/mL; P < 0.0001), respectively. Multiple linear regression showed that NGAL levels were independently related to the severity of AKI and the extent of systemic inflammation. NGAL levels were higher in non-survivors (430 [303-942] ng/mL) compared to survivors (298 [159-506] ng/mL; P = 0.004). Consistently, Cox proportional hazards regression analysis identified NGAL as a strong independent predictor for 28-day survival (hazard ratio 1.6 (95% confidence interval [CI] 1.15 - 2.23), P = 0.005).ConclusionsThis is the first prospective evaluation of serum NGAL as an outcome-specific biomarker in critically ill patients at initiation of RRT. The results from this study indicate that serum NGAL is as an independent predictor of 28-day mortality in ICU patients with dialysis-dependent AKI.

Pharmacokinetics and total elimination of meropenem and vancomycin in intensive care unit patients undergoing extended daily dialysis

Objective:Extended daily dialysis (EDD) combines the advantage of both intermittent hemodialysis and continuous renal replacement therapy: excellent detoxification accompanied by cardiovascular tolerability. The aim of this study was to evaluate pharmacokinetics of meropenem and vancomycin in critically ill patients with renal failure undergoing EDD. Design:Prospective clinical study. Setting:Surgical intensive care unit in a tertiary care center. Patients:We studied intensive care patients with anuric acute renal failure being treated with EDD and receiving meropenem (n = 10) or vancomycin (n = 10) therapy. Interventions:The antibiotics were administered 6 hrs (1.0 g meropenem) or 12 hrs (1.0 g vancomycin) before EDD was started in order to study the pharmacokinetics before and during EDD. In addition to the application of different methods to calculate pharmacokinetic parameters, the total dialysate concentration of both drugs was measured. Results:Based on the amount of the drug recovered from the collected spent dialysate, the fraction of drug removed by one dialysis treatment was 18% for meropenem and 26% for vancomycin. Dosing regimes for intermittent hemodialysis and continuous renal replacement therapy cannot be used for critically ill patients treated with EDD. Conclusion:Our data suggest that patients treated with EDD by means of a high-flux dialyzer (polysulphone; surface area, 1.3 m2; blood and dialysate flow, 160 mL/min; EDD time, 480 mins) and current dosing regimens run the risk of being significantly underdosed, which may have detrimental effects on critically ill patients with life-threatening infections. The exact dose has to be tailored according to weight and severity of illness as well as the current minimal inhibitory concentration against the incriminated bacteria. Whenever possible, therapeutic drug monitoring should be performed.

Renal function and survival in 200 patients undergoing ECMO therapy

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is increasingly used in the intensive care unit (ICU) setting to improve gas exchange in patients with acute respiratory distress syndrome as well as in patients pre- and post-heart and lung transplantation. In this clinical setting, acute kidney injury (AKI) is frequently observed. So far, it is unknown how AKI affects the survival of critically ill patients receiving ECMO support and whether veno-veno and veno-arterial ECMO have different effects on kidney function. METHODS This is a retrospective analysis of patients undergoing ECMO treatment in medical and surgical ICUs in a tertiary care centre. We evaluated all patients undergoing ECMO treatment at our centre between 1 January 2005 and 31 December 2010. Data from all 200 patients (83F/117M), median age 45 (17-83) years, were obtained by chart review. Follow-up data were obtained for up to 3 months. RESULTS Three-month survival of all patients was 31%. Of the 200 patients undergoing ECMO treatment, 60% (120/200) required renal replacement therapy (RRT) for AKI. While patients without RRT showed a 3-month survival of 53%, the survival of patients with AKI requiring RRT was 17% (P = 0.001). Longer duration of RRT was associated with a higher mortality. CONCLUSIONS AKI requiring RRT therapy in patients undergoing ECMO treatment increases mortality in ICU patients. Future studies have to clarify whether it is possible to identify patients who benefit from the combination of ECMO and RRT.

Pharmacokinetics of Moxifloxacin and Levofloxacin in Intensive Care Unit Patients Who Have Acute Renal Failure and Undergo Extended Daily Dialysis

Extended daily dialysis (EDD) is increasingly popular in the treatment of acute renal failure (ARF). EDD could remove drugs to a much different degree compared with intermittent standard hemodialysis or continuous renal replacement therapies; however, there are only scarce data on how EDD influences the pharmacokinetics of frequently used drugs. The aim of this study was to determine the pharmacokinetics of two quinolone antibiotics in patients who had anuric ARF and were being treated with EDD. Adult patients who were in the intensive care unit at a tertiary care university hospital and receiving moxifloxacin (n = 10) or levofloxacin (n = 5) therapy were included. The antibiotics were administered intravenously 8 h (400 mg of moxifloxacin) or 12 h (500 mg of levofloxacin) before EDD to study pharmacokinetics off and on EDD. Treatment lasted 8 h; blood and dialysate flow rates were 160 ml/min. In addition to standard pharmacokinetic parameters, the total dialysate concentration of both drugs was measured using a technically simple single-pass batch dialysis system for EDD. Moxifloxacin pharmacokinetics in critically ill patients who had ARF and were undergoing EDD were similar to those in healthy subjects without renal impairment. Levofloxacin, although removed by EDD, had a lower total clearance compared with healthy subjects. According to these findings, anuric critically ill patients who are undergoing EDD should be treated with the standard dosage of moxifloxacin (400 mg/d intravenously). The levofloxacin dosage, however, should be reduced according to the intensity of renal replacement therapy.