How to Define Acute Liver Failure Patients with Pre-Existing Liver Disease without Signs of Cirrhosis.

BACKGROUND: The definition of acute liver failure (ALF) usually implies no previous liver injury. Though, some patients admitted to liver transplantation centers with the diagnosis of ALF are obese or have diabetes. Elevated liver enzymes were not recorded previously, and no signs of cirrhosis or prior decompensation of the liver function were ever present. Still, these patients differ from the "typical" ALF-patient. GOALS: In this study, we aimed to confirm acute-on-chronic-liver failure (AOCLF) in patients diagnosed with ALF and to identify possible differences between ALF and AOCLF. STUDY: Patients were retrospectively recruited from all patients admitted to the University Hospital Essen with diagnosis of ALF between 2008 and 2015. Data of 163 patients were evaluated, resulting in a reclassification of 32 patients as AOCLF (remaining ALF: 131). Demographic and clinical data as well as serum parameters, including cell death markers, were correlated with clinical outcome. RESULTS: Patients with AOCLF were significantly older, had a higher body mass index (BMI), and were more often male. The cause for liver failure in these patients differed significantly from patients who had an actual ALF. Significant differences were also found for serum liver enzymes. Outcome of patients did not differ between AOCLF and ALF. Though, lower BMI and MELD and higher AST and GLDH were predictors for a beneficial outcome. CONCLUSION: AOCLF is still commonly misdiagnosed as ALF. While clinical outcome does not significantly differ between ALF and AOCLF, risk factors for adverse outcome may significantly differ between these entities.

Therapeutic plasma exchange in acute liver failure.

BACKGROUND: Multi-organ dysfunction in acute liver failure (ALF) has been attributed to a systemic inflammatory response directly triggered by the injured liver. High-volume therapeutic plasma exchange (HV-TPE) has been demonstrated in a large randomized controlled trial to improve survival. Here, we investigated if a more cost-/ resource effective low-volume (LV) TPE strategy might have comparable beneficial effects. METHODS: This retrospective study evaluated the effect of LV-TPE on remote organ failure, hemodynamical and biochemical parameters as well as on survival in patients with ALF. Twenty patients treated with LV-TPE in addition to standard medical therapy (SMT) were identified and 1:1 matched to a historical ALF cohort treated with SMT only. Clinical and biochemical parameters were recorded at admission to the intensive care unit and the following 7 days after LV-TPE. RESULTS: Mean arterial pressure increased following first LV-TPE treatments (d0: 68 [61-75] mm Hg vs d7: 88 [79-98] mm Hg, P = .003) and norepinephrine dose was reduced (d0: 0.264 [0.051-0.906] µg/kg/min vs d3: 0 [0-0.024] µg/kg/min, P = .016). Multi-organ dysfunction was significantly diminished following LV-TPE (CLIF-SOFA d0: 17 [13-20] vs d7: 7 [3-11], P = .001). Thirty-day in-hospital survival was 65% in the LV-TPE cohort and 50% in the SMT cohort (Hazard-ratio for TPE: 0.637; 95% CI: 0.238-1.706, P = .369). CONCLUSIONS: Patients treated with LV-TPE showed improved surrogate parameters comparable with the effects reported with HV-TPE. These data need to be interpreted with caution due to their retrospective character. Future controlled studies are highly desirable.

MicroRNAs play a role in spontaneous recovery from acute liver failure.

UNLABELLED: Acute liver failure (ALF) represents a life-threatening situation characterized by sudden and massive liver cell death in the absence of preexisting liver disease. Although most patients require liver transplantation to prevent mortality, some recover spontaneously and show complete liver regeneration. Because of the rarity of this disease, the molecular mechanisms regulating liver regeneration in ALF patients remain largely unknown. In this study, we investigated the role of microRNAs (miRs) that have been implicated in liver injury and regeneration in sera from ALF patients (n = 63). Patients with spontaneous recovery from ALF showed significantly higher serum levels of miR-122, miR-21, and miR-221, compared to nonrecovered patients. In liver biopsies, miR-21 and miR-221 displayed a reciprocal expression pattern and were found at lower levels in the spontaneous survivors, whereas miR-122 was elevated in both serum and liver tissue of those patients. As compared to nonrecovered patients, liver tissue of spontaneous survivors revealed not only increased hepatocyte proliferation, but also a strong down-regulation of miRNA target genes that impair liver regeneration, including heme oxygenase-1, programmed cell death 4, and the cyclin-dependent kinase inhibitors p21, p27, and p57. CONCLUSION: Our data suggest that miR-122, miR-21, and miR-221 are involved in liver regeneration and might contribute to spontaneous recovery from ALF. Prospective studies will show whether serological detection of those miRNAs might be of prognostic value to predict ALF outcome.

Aortic Valve Replacement in Patients with End-Stage Liver Disease: A Modified Perfusion Concept in High-Risk Patients.

BACKGROUND AND AIM OF THE STUDY: Cardiac surgery with the use of cardiopulmonary bypass in patients with end-stage liver disease is associated with a high risk of postoperative morbidity and mortality due to bleeding, and a high incidence of bacterial infection with associated secondary complications. Minimized extracorporeal perfusion circuits (MECCs) with a lower priming volume, reduced foreign surface area, and interdisciplinary preoperative and postoperative treatment may address these negative effects and improve patient outcomes. The study aim was to evaluate the feasibility of the MECC and optimized supportive therapy in patients with advanced-stage liver cirrhosis. METHODS: Seven consecutive male patients (median age 56 years; range 54-67 years) with hepatic cirrhosis (Child-Pugh score B, median Model of End-stage Liver Disease (MELD) score 14; range 8-26) underwent aortic valve replacement (AVR) using MECC. Supportive preoperative and postoperative management included digestive decontamination, antioxidant supplements, and adjusted anti-infective therapy. RESULTS: All patients survived the hospital course, with 30-, 60-, and 90-day mortality of 0%. The median intensive care unit and in-hospital lengths of stay were 3 days (range: 1-5 days) and 13 days (range: 5-18 days), respectively. One patient required reexploration due to bleeding, and another suffered from a seizure without permanent neurologic deficits. No patient required new-onset hemodialysis. At a median follow up of 22 months (range: 2-46 months) all patients were alive but displayed only minor improvements in cardiac symptoms (median NYHA class III (range: II-III) at baseline versus II (range: II-III) postoperatively) and hepatic symptoms. CONCLUSION: Conventional AVR in patients with advanced-stage liver cirrhosis using MECC and optimal medical treatment is feasible. Further studies are required to evaluate the impact of alternative interventional techniques in this high-risk cohort.

Monitoring of patients supported by extracorporeal membrane oxygenation for systemic infections by broad-range rRNA gene PCR amplification and sequence analysis.

The rRNA gene PCR and sequencing test, SepsiTest, was compared with blood culture (BC) regarding the diagnosis of pathogens in 160 blood samples drawn from 28 patients during extracorporeal membrane oxygenation. With 45% of positive samples, SepsiTest was 13 to 75 h faster than BC. SepsiTest indicated bacteremias in 25% of patients who were BC negative.

Removal characteristics and total dialysate content of glutamine and other amino acids in critically ill patients with acute kidney injury undergoing extended dialysis.

BACKGROUND: Acute kidney injury in critically ill patients is associated with the activation of protein catabolism and a negative nitrogen balance. Renal replacement therapy (RRT) aggravates this problem by eliminating a substantial amount of amino acids. However, there is scarce data on the removal characteristics of modern dialysis membranes in extended dialysis. METHODS: This is a prospective study in 10 extended dialysis sessions using a 1.8-m(2) polysulfone membrane (EMiC2 dialyzer or AV 1000S; FMC, Germany). Blood samples for 19 amino acids were drawn before, during, and after 10 h of extended dialysis (blood/dialysate flow 150 ml/min). In addition, samples for the calculation of dialyzer clearance and samples from the total spent dialysate were measured using a Biochrom 30 amino acid analyzer. RESULTS: Despite no significant difference in pre- and postdialysis plasma amino acid levels, we found an impressive amount of amino acids in collected spent dialysate, i.e. 10.5 g/10 h of treatment. The dialyzer clearance ranged from 67.6 ml/min for phenylalanine to 140.0 ml/min for valine. The total eliminated masses of the measured amino acids had equal values for both membranes. There was a significant difference between the dialyzer clearance of the investigated membranes for glutamine (AV 1000S: 83.3 ml/min vs. EMiC2: 92.0 ml/min, p = 0.02) and serine (88.8 ml/min vs. 91.8 ml/min, p = 0.005). DISCUSSION: Our data indicate that the modern forms of RRT eliminate amino acids to an extent that has not been met by our nutritional support standards. Especially the removal of glutamine, important for immune function and cell regeneration, might have detrimental effects on the recovery of critically ill patients.

Therapeutic plasma exchange as rescue therapy in severe sepsis and septic shock: retrospective observational single-centre study of 23 patients.

BACKGROUND: Several case series and small randomized controlled trials suggest that therapeutic plasma exchange (TPE) improves coagulation, hemodynamics and possibly survival in severe sepsis. However, the exact role of TPE in modern sepsis therapy remains unclear. METHODS: We performed a retrospective observational single-centre study on the use of TPE as rescue therapy in 23 consecutive patients with severe sepsis or septic shock from 2005 to 2012. Main surrogate markers of multiple organ failure (MOF) before, during and after TPE as well as survival rates are reported. RESULTS: At baseline, mean SOFA score was 13 (standard deviation [SD] 4) and median number of failed organ-systems was 5 (interquartile range [IQR] 4-5). TPEs were performed 3 days (IQR 2-10) after symptom onset and 1 day (IQR 0-8) after ICU admission. The median total exchange volume was 3750 ml (IQR 2500-6000), which corresponded to a mean of 1.5 times (SD 0.9) the individual plasma volume. Fresh frozen plasma was used in all but one treatments as replacement fluid. Net fluid balance decreased significantly within 12 hrs following the first TPE procedure by a median of 720 mL (p = 0.002), irrespective of outcome. Reductions of norepinephrine dose and improvement in cardiac index were observed in individual survivors, but this was not significant for the overall cohort (p = 0.574). Platelet counts decreased irrespective of outcome between days 0 and 2 (p < 0.003), and increased thereafter in many survivors. There was a non-significant trend towards younger age and higher procalcitonin levels among survivors. Nine out of 23 TPE treated patients (39%) survived until ICU discharge (among them 3 patients with baseline SOFA scores of 15, 17, and 20). CONCLUSIONS: Our data suggest that some patients with severe sepsis and septic shock may experience hemodynamic stabilisation by early TPE therapy.

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.

Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation.

RATIONALE: The use of extracorporeal membrane oxygenation (ECMO) in patients who are awake and spontaneously breathing may represent a novel bridging strategy toward lung transplantation (LuTx). OBJECTIVES: To evaluate the outcomes of patients treated with the "awake ECMO" concept as bridge to transplantation. METHODS: We performed a retrospective, single-center, intention-to-treat analysis of consecutive LuTx candidates with terminal respiratory or cardiopulmonary failure receiving awake ECMO support. The outcomes were compared with a historical control group of patients treated with conventional mechanical ventilation (MV group) as bridge to transplant. MEASUREMENTS AND MAIN RESULTS: Twenty-six patients (58% female; median age, 44 yr; range, 23-62) were included in the awake ECMO group and 34 patients (59% female; median age, 36 yr; range, 18-59) in the MV group. The duration of ECMO support or MV, respectively, was comparable in both groups (awake ECMO: median, 9 d; range, 1-45. MV: median, 15 d; range, 1-71; P = 0.25). Six (23%) of 26 patients in the awake ECMO group and 10 (29%) of 34 patients in the MV group died before a donor organ was available (P = 0.20). Survival at 6 months after LuTx was 80% in the awake ECMO group versus 50% in the MV group (P = 0.02). Patients in the awake ECMO group required shorter postoperative MV (P = 0.04) and showed a trend toward a shorter postoperative hospital stay (P = 0.06). CONCLUSIONS: ECMO support in patients who are awake and nonintubated represents a promising bridging strategy, which should be further evaluated to determine its role in patients with end-stage lung disease awaiting LuTx.

Etiologies and outcomes of acute liver failure in Germany.

BACKGROUND & AIMS: Acute liver failure (ALF) is a severe form of acute liver injury that can progress to multiple organ failure. We investigated causes and outcomes of ALF. METHODS: Eleven university medical centers in Germany were asked to report patients with (primary) severe acute liver injury (sALI) (international normalized ratio [INR] >1.5 but no hepatic encephalopathy) and primary ALF (INR >1.5 with overt hepatic encephalopathy) treated from 2008 to 2009. Data were analyzed from 46 patients with sALI and 109 patients with ALF. RESULTS: The most frequent etiologies of primary ALF were non-acetaminophen drug-induced (32%), indeterminate (24%), and viral (21%); acetaminophen ingestion was the cause of ALF in only 9% of patients. The support of a ventilator was required by 44% of patients with ALF, vasopressors by 38%, and renal replacement by 36%. Seventy-nine patients with ALF (72%) survived until hospital discharge, 38 (35%) survived without emergency liver transplantation (ELT), and 51 received ELT (47%); 80% of patients who received ELT survived until discharge from the hospital. CONCLUSIONS: In Germany, drug toxicity, indeterminate etiology, and viral hepatitis appear to be the major causes of primary ALF, which has high mortality. Patients with ALF are at great risk of progressing to multiple organ failure, but 80% of patients who receive ELT survive until discharge from the hospital.

Angiopoietin-2 in acute liver failure.

OBJECTIVE: Angiopoietin-2, an antagonistic ligand of the endothelial Tie2 receptor, has been identified as a gatekeeper of endothelial activation. We examined whether the release of Angiopoietin-2 correlates with surrogates of organ dysfunction and outcome in patients with acute liver failure. DESIGN: Retrospective clinical and immunohistological study. SETTING: Intensive care unit of a university hospital. PATIENTS: Thirty-seven patients with acute liver failure and 20 healthy control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Angiopoietin-2 levels were measured in sera from 37 patients with acute liver failure on admission and from 20 healthy control subjects. Median age of patients with acute liver failure was 34 yrs, 29 were female, and 21 developed encephalopathy grade 3 or greater. Nine patients survived to day 28 without transplantation, five died without transplantation, and 23 received a transplant. Median (interquartile range) Angiopoietin-2 serum concentrations steadily increased across the following groups: healthy control subjects (1.4 [0.9-1.7] ng/mL), patients with transplant-free recovery (10.0 [4.7-12.1] ng/mL), and patients who reached the composite end point of death or emergency liver transplantation (16.8 [11.3-39.5] ng/mL). Angiopoietin-2 release correlated strongly with surrogate markers of organ dysfunction and disease severity measures (lactate, platelet count, Sequential Organ Failure Assessment score, and Simplified Acute Physiology Score III). Angiopoietin-2 levels were higher in patients with acute kidney injury and patients on mechanical ventilation. Furthermore, Angiopoietin-2 levels were closely associated with Bilirubin-Lactate-Etiology score but not with other liver-specific markers. Unadjusted and adjusted Cox's proportional hazards analyses identified Angiopoietin-2 as a predictor of the composite end point of death or transplantation. Finally, immunohistological studies showed that Angiopoietin-2 protein was upregulated in acute liver failure explants compared with matched liver biopsies obtained at baseline. CONCLUSIONS: Collectively, our data show that circulating Angiopoietin-2, which potentially originates from the injured liver, correlates with several features of multiple organ dysfunction syndrome and independently predicts outcome. Tie2 agonists may have potential as an endothelium-targeted therapy to ameliorate multiple organ dysfunction syndrome and improve outcome in acute liver failure.

New high-cutoff dialyzer allows improved middle molecule clearance without an increase in albumin loss: a clinical crossover comparison in extended dialysis.

BACKGROUND: Accumulation of middle molecules is thought to have adverse effects in patients with acute kidney injury (AKI). Elimination of middle molecules by non-convective means, i.e. hemodialysis, remains difficult. The aim of the study was to investigate the removal characteristics of a new high permeability membrane in AKI patients undergoing extended dialysis (ED). PATIENTS AND METHODS: We performed a prospective, crossover study comparing the EMiC2 dialyzer (1.8 m(2), FMC, Germany) and AV 1000S (1.8 m(2), FMC) in 11 critically ill patients with AKI. ß2-Microglobulin, cystatin c, creatinine, and urea were measured before and after 0.5, 5.0 and 10 h of ED. Serum reduction ratios, dialyzer clearances, and mass in the total collected dialysate were determined. RESULTS: Dialyzer clearance of ß2-microglobulin (EMiC2: 52 ± 1.7 ml/min, AV 1000S: 41.7 ± 1.5 ml/min, p = 0.0002) and cystatin c (EMiC2: 47.2 ± 1.2 ml/min, AV 1000S: 34.2 ± 2.3 ml/min, p < 0.0001) was markedly different, as was the reduction of serum levels of ß2-microglobulin (EMiC2: 54.3 ± 3.6%, AV 1000S: 39.1 ± 4.5%, p = 0.025) and cystatin c (EMiC2: 38.9 ± 2.6%, AV 1000S: 28.0 ± 3.9%, p = 0.043). Additionally, we observed a higher total amount of these substances in the collected dialysate. There was no significant difference in the total amount of albumin eliminated per treatment. CONCLUSION: The new EMiC2 dialyzer enhances removal of middle molecules without an increase in albumin loss. The clinical relevance of this finding needs to be determined.

Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection.

BACKGROUND & AIMS: Pegylated interferon-alpha (PEG-IFNalpha), in combination with ribavirin, controls hepatitis C virus (HCV) infection in approximately 50% of patients by mechanisms that are not completely understood. Beside a direct antiviral effect, different immunomodulatory effects have been discussed. Natural killer (NK) cells might be associated with control of HCV infection. We examined the effects of IFNalpha on human NK cells and its relevance to HCV infection. METHODS: We performed gene expression profiling studies of NK cells following stimulation of peripheral blood mononuclear cells with IFNalpha. We evaluated IFNalpha-induced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression using flow cytometry analyses of NK cells isolated from patients with acute or chronic hepatitis C that had received PEG-IFNalpha therapy. RESULTS: TRAIL was among the most up-regulated genes after IFNalpha stimulation of NK cells from healthy controls. After in vitro stimulation with IFNalpha, CD56(dim) NK cells from patients who had responded to PEG-IFNalpha therapy expressed higher levels of TRAIL than cells from patients with chronic hepatitis C. TRAIL expression, ex vivo, was inversely correlated with HCV-RNA levels during the early phase of PEG-IFNalpha therapy. In patients with acute hepatitis C, TRAIL expression on CD56(bright) NK cells increased significantly compared with cells from controls. In in vitro studies, IFNalpha-stimulated NK cells eliminated HCV-replicating hepatoma cells by a TRAIL-mediated mechanism. CONCLUSIONS: IFNalpha-induced expression of TRAIL on NK cells is associated with control of HCV infection; these observations might account for the second-phase decline in HCV-RNA levels during PEG-IFNalpha therapy.

Liver transplantation: A new risk factor for intestinal intussusceptions.

BACKGROUND: Intestinal intussusception in adults is associated with chronic inflammatory bowel disease, celiac disease, abdominal tumors or previous abdominal surgery but most often of unknown origin. AIM: The aim of our study was to evaluate circumstances and identify risk factors for intussusceptions. METHODS: All 65,928 abdominal ultrasound examinations performed at our tertiary medical center between January 2001 and June 2008 were analyzed retrospectively for the diagnosis "intussusception". After identifying individuals with sonographically proven intussusception we analyzed various patients' characteristics including age, gender and underlying disease as well as sonographic findings such as localization of the intussusception, absence or presence of ascites and lymph nodes. RESULTS: We identified 32 cases of intussusceptions [mean age 45 years (range 18 to 88); 18 patients were male]. Twelve patients (38%) had a history of abdominal surgery including 8 patients who had undergone liver transplantation (2 patients with primary sclerosing cholangitis, 1 patient with cystic fibrosis, 1 patient with sarcoidosis, 1 patient with hepatocellular carcinoma and HCV infection, 1 patient with autoimmune hepatitis, 1 patient with Crigler-Najar-syndrome and one patient with echinococcus). A hepaticojejunostomy had been performed in 4 of the patients after liver transplantation. Liver transplanted patients were significantly overrepresented in the intussusceptions group compared with the overall cohort of patients undergoing abdominal ultrasound examination (25% vs. 8%, Chi-Square-test, p = 0.0023). CONCLUSION: In our retrospective study liver transplantation, in particular with hepaticojejunostomy, was identified as a new major risk factor for intestinal intussusceptions

Effect of acute kidney injury requiring extended dialysis on 28 day and 1 year survival of patients undergoing interventional lung assist membrane ventilator treatment.

BACKGROUND: Extracorporeal lung assist devices are increasingly used in the intensive care unit setting to improve extracorporeal gas exchange mainly in patients with acute respiratory distress syndrome. ARDS is frequently accompanied by acute kidney injury; however it is so far unknown how the combination of these two conditions affects long term survival of critically ill patients. METHODS: In a retrospective analysis of a tertiary care hospital we evaluated all patients undergoing interventional lung assist (iLA) treatment between January 1st 2005 and December 31st 2009. Data from all 61 patients (31 F/30 M), median age 40 (28 to 52) years were obtained by chart review. Follow up data up to one year were obtained. RESULTS: Of the 61 patients undergoing iLA membrane ventilator treatment 21 patients had acute kidney injury network (AKIN) stage 3 and were treated by extended dialysis (ED). Twenty-eight day survival of all patients was 33%. While patients without ED showed a 28 day survival of 40%, the survival of patients with ED was only 19%. Patients on ED were not different in respect to age, weight, Horowitz index and underlying disease. CONCLUSIONS: AKI requiring ED therapy in patients undergoing iLA treatment increases mortality in ICU patients. Patients in whom iLA was placed as a bridge to lung transplantation and that were successfully transplanted showed the best outcome. Future studies have to clarify whether it is possible to identify patients that truly benefit from the combination of these two extracorporeal treatment methods.

Caspase activation is associated with spontaneous recovery from acute liver failure.

UNLABELLED: Acute liver failure (ALF) has various causes and is characterized by rapid hepatocyte dysfunction with development of encephalopathy in the absence of preexisting liver disease. Whereas most patients require liver transplantation to prevent the high mortality, some patients recover spontaneously and show complete liver regeneration. Because of the low incidence of ALF, however, the molecular mechanisms of liver dysfunction and regeneration are largely unknown. In this study, we investigated the role of apoptosis and caspases in 70 ALF patients using novel biomarkers that allow the detection of caspase activation in serum samples. Compared with healthy individuals, activation of caspases was strongly enhanced in ALF patients. Interestingly, patients with spontaneous recovery from ALF revealed a significantly higher activation of caspases than patients that required transplantation or died, although in the latter patients extensive DNA fragmentation and signs of nonapoptotic cell death were observed. In the spontaneous survivors, increased caspase activation was accompanied by elevated levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6), important cytokines involved in liver regeneration. CONCLUSION: Our data suggest that caspase activation and apoptosis are involved in ALF of patients with spontaneous recovery, whereas caspase-independent cell death might be more relevant in irreversible forms of liver failure. These findings might be important for therapeutic options of ALF but also suggest that measurement of caspase activation might be of prognostic value to predict the outcome of acute liver failure.

Outcomes of renal dysfunction in patients with acute liver failure.

Background: Although acute kidney injury (AKI) often accompanies acute liver failure (ALF), its impact on long-term outcome is unknown. Objective: This study examines the incidence, severity and outcomes of AKI in patients with ALF. Methods: A total of 134 ALF patients treated at Hannover Medical School between 1995 and 2013 were retrospectively analyzed. Results: Fifty-four ALF patients (40.3%) demonstrated AKI, as defined by the acute kidney injury network (AKIN) classification, on intensive care unit (ICU) admission, and 85 patients (63.4%) developed AKI prior to ALF recovery, emergency liver transplantation (ELT) or death. AKI severity was closely associated with other end-organ damage (p < 0.001). Follow-up creatinine levels in survivors were increased compared to baseline levels (76 versus 64 µmol/l, p = 0.003). One-hundred-and-three (76.9%) patients reached the combined endpoint of ELT or death, and 42 (31.3%) patients died within 28 days. AKIN stage 3 at ICU admission was the strongest independent predictor of 28-day overall mortality (hazard ratio 3.48, 95% confidence interval 1.75-6.93, p < 0.001) and ELT or death (hazard ratio 2.52, 95% confidence interval 1.60-3.96, p < 0.001). Conclusions: AKI is a frequent complication in ALF that correlates with remote organ damage and long-term creatinine levels and independently predicts outcome.

Prognostic implications of lactate, bilirubin, and etiology in German patients with acute liver failure.

BACKGROUND & AIMS: Among the potentially helpful indicators of poor prognosis in acute liver failure (ALF) are etiology, encephalopathy grade, blood lactate, and King's College Criteria (KCC). The accuracy of these parameters in predicting transplantation or death shows significant variation in different countries. METHODS: We retrospectively analyzed 102 patients with ALF treated at our institution between 1996 and 2005. Baseline parameters, simplified acute physiology score III (SAPS-III), KCC, Model for End-Stage Liver Disease (MELD) score, and a novel score of bilirubin, lactate, and etiology (BiLE score) were compared between transplant-free survivors and patients who required liver transplantation or died, by using multivariate linear regression analysis and receiver operating characteristics (ROC). RESULTS: The most common causes of ALF were indeterminate liver failure (21%), acute hepatitis B (18%), acetaminophen ingestion (16%), and Budd-Chiari syndrome (9%). Transplantation-free survival was 38%, 44% of patients underwent liver transplantation, and 18% died without transplantation. Eight-week survival was 77%. The BiLE score was the best predictor of death or need of transplantation, with 79% sensitivity and 84% specificity. ROC analysis revealed a better performance of BiLE score when compared with bilirubin, lactate, MELD score, and SAPS-III (area under the curve: 0.87 +/- 0.04, 0.73 +/- 0.51, 0.73 +/- 0.52, 0.71 +/- 0.05, and 0.68 +/- 0.59, respectively). CONCLUSIONS: The simple, combined BiLE score emerged as the best predictor of poor outcome in our patient cohort and should be prospectively evaluated in other populations.

Antibody to hepatitis B surface antigen trough levels and half-lives do not differ after intravenous and intramuscular hepatitis B immunoglobulin administration after liver transplantation.

Hepatitis B immunoglobulin (HBIG) administration remains an essential component of standard reinfection prophylaxis after liver transplantation for hepatitis B virus-related liver disease. Previous studies have suggested that intramuscular (IM) HBIG administration compared to intravenous (IV) HBIG administration may be cost-effective and dose-saving. To compare antibody against hepatitis B surface antigen (anti-HBs) kinetics after IV HBIG administration versus IM HBIG administration, 24 patients received 2000 IU of HBIG every 6 weeks over a study period of 48 weeks in a crossover design. HBIG was started intravenously in 12 patients (group A) and intramuscularly in 12 patients (group B). After 4 doses, at week 24 HBIG administration was switched from IM to IV and vice versa. Anti-HBs kinetics of 22 patients were evaluated. Mean anti-HBs levels measured 2, 4, and 6 weeks after each HBIG administration did not differ significantly (480 +/- 166, 319 +/- 126, and 221 +/- 106 IU/L after IV administration versus 457 +/- 166, 310 +/- 147, and 218 +/- 112 IU/L after IM administration). Half-lives of anti-HBs decline (IV, 25.5 +/- 6.0 days, versus IM, 24.7 +/- 6.2 days) and area under the curve values from week 2 to 6 (IV, 9.4 +/- 3.6 IU*day/mL, versus IM, 9.0 +/- 3.9 IU*day/mL) also showed no significant difference. Variation of anti-HBs levels after IV HBIG administration versus IM HBIG administration was neither significantly different within patients (intraindividual variance) nor between patients (interindividual variance). However, intraindividual variance was lower than interindividual variance after IV (P < 0.05) and IM (P < 0.05) HBIG administration at every time point (2, 4, and 6 weeks). In conclusion, IV HBIG administration and IM HBIG administration are equally effective with respect to the crucial pharmacokinetic parameters. That is, IM HBIG is not dose-saving; however, it may be cost-effective if the price per unit is lower. Individualized dosing intervals should be further evaluated as a cost-effective alternative to fixed dosing schemes.