Johannes Hadem

Extracorporeal Membrane Oxygenation in Nonintubated Patients as Bridge to Lung Transplantation

We report on the use of veno‐arterial extracorporeal membrane oxygenation (ECMO) as a bridging strategy to lung transplantation in awake and spontaneously breathing patients. All five patients described in this series presented with cardiopulmonary failure due to pulmonary hypertension with or without concomitant lung disease. ECMO insertion was performed under local anesthesia without sedation and resulted in immediate stabilization of hemodynamics and gas exchange as well as recovery from secondary organ dysfunction. Two patients later required endotracheal intubation because of bleeding complications and both of them eventually died. The other three patients remained awake on ECMO support for 18–35 days until the time of transplantation. These patients were able to breathe spontaneously, to eat and drink, and they received passive and active physiotherapy as well as psychological support. All of them made a full recovery after transplantation, which demonstrates the feasibility of using ECMO support in nonintubated patients with cardiopulmonary failure as a bridging strategy to lung transplantation.

Interferon-α–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.

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

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‐α) 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. (HEPATOLOGY 2008.)

Failure of hepatitis B vaccination with conventional HBsAg vaccine in patients with continuous HBIG prophylaxis after liver transplantation

Hepatitis B vaccination after liver transplantation for hepatitis B–related liver disease has been investigated as an alternative strategy to reinfection prophylaxis with hepatitis B immunoglobulin (HBIG) with conflicting results. In most studies, HBIG treatment was discontinued before vaccination. An outstanding good response was achieved with vaccination under continuous HBIG administration using hepatitis B surface antigen (HBsAg)‐based vaccine containing special adjuvants. Both, adjuvants and continuous HBIG administration have been discussed as crucial factors for good response. Twenty‐four patients were vaccinated with conventional double dose recombinant vaccine containing 40 μg HBsAg up to 12 times at weeks 0, 2, 4 (cycle 1), 12, 14, 16 (cycle 2), 24, 26, 28 (cycle 3), and 36, 38, 40 (cycle 4). All patients received 2,000 IU HBIG every 6 weeks (4 times intravenously and 4 times intramuscularly). A significant response was defined as reconfirmed increase of anti‐HBs‐antigen (anti‐HBs) unexplained by HBIG administration or lack of anti‐HBs decrease below 100 IU/L after discontinuation of HBIG treatment after week 48. Only 2 of 24 patients (8.3%) responded significantly. Anti‐HBs started to increase after the seventh vaccination (cycle 3, during intramuscular HBIG administration) in 1 patient and after 12th vaccination (cycle 4, during intravenous HBIG administration) in the other. Maximum anti‐HBs levels were >1,000 IU/L in both patients and decreased significantly slower as compared to passive prophylaxis during follow‐up. In conclusion, the conventional HBsAg vaccine failed to induce a significant humoral immune response in most patients despite continued HBIG treatment. Further studies should address the question, of whether the use of potent adjuvant systems results in higher response rates. Liver Transpl 13: 367–373, 2007.

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.

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.

Acute liver failure: a life-threatening disease.

BACKGROUND An estimated 200 to 500 patients develop life-threatening acute liver failure (ALF) in Germany each year. Only sparse data are currently available on the epidemiology and causes of this condition and on potential treatments for it. This article summarizes our current knowledge of the causes, clinical course, and treatment of ALF. METHOD We selectively reviewed the pertinent current literature on ALF from Germany and abroad. RESULTS A shift is currently taking place in Germany with respect to the predominant causes of ALF: The leading cause was formerly acute viral hepatitis, but now more cases of ALF are induced by toxic substances, while there is also a growing incidence of cryptogenic subacute ALF. Precise epidemiological data are still lacking. Scoring -systems for the assessment of ALF should take account of hepatic function, the regenerative capacity of the liver, the extent of existing extrahepatic complications, and the risk that further ones will develop. The mortality from ALF has been reduced through improved specific treatment for certain etiological types of ALF, the introduction of liver transplantation, and progress in intensive care medicine. The optimal treatment of ALF patients requires close collaboration among specialists in all of the involved clinical disciplines, as well as between peripheral hospitals and transplantation centers. CONCLUSION Precise epidemiological data on ALF are still lacking in Germany, as are prospective, randomized trials of treatments for it. It is nonetheless clear that progress has been made in its diagnosis and treatment.

Lung transplantation for severe pulmonary hypertension--awake extracorporeal membrane oxygenation for postoperative left ventricular remodelling.

Background Bilateral lung transplantation (BLTx) is an established treatment for end-stage pulmonary hypertension (PH). Ventilator weaning failure and death are more common as in BLTx for other indications. We hypothesized that left ventricular (LV) dysfunction is the main cause of early postoperative morbidity or mortality and investigated a weaning strategy using awake venoarterial extracorporeal membrane oxygenation (ECMO). Methods In 23 BLTx for severe PH, ECMO used during BLTx was continued for a minimum of 5 days (BLTx-ECMO group). Echocardiography, left atrial (LA) and Swan-Ganz catheters were used for monitoring. Early extubation after transplantation was attempted under continued ECMO. Results Preoperatively, all patients had severely reduced cardiac index (mean, 2.1 L/min/m2). On postoperative day 2, reduction of ECMO flow resulted in increasing LA and decreasing systemic blood pressures. On the day of ECMO explantation (median, postoperative day 8), LV diameter had increased; LA and blood pressures remained stable. Survival rates at 3 and 12 months were 100% and 96%, respectively. Data were compared to two historic control groups of BLTx without ECMO (BLTx ventilation) or combined heart-lung transplantation for severe PH. Conclusion Early after BLTx for severe PH, the LV may be unable to handle normalized LV preload. This can be effectively bridged with awake venoarterial ECMO.

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 Kings 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.

MicroRNAs play a role in spontaneous recovery from acute liver failure

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. (Hepatology 2014;60:1346–1355)