Claus Georg Krenn

Comparison of invasive and noninvasive measurement of plasma disappearance rate of indocyanine green in patients undergoing liver transplantation: A prospective investigator-blinded study

Plasma disappearance rate of indocyanine green (PDRICG) has been proposed for assessment of liver function in liver transplants donors and recipients, in patients with chronic liver failure, and as a prognostic factor in critically ill patients. The assessment of PDRICG using a newly developed noninvasive digital pulse densitometry method was simultaneously compared to invasive aortic fiber‐optic method in patients undergoing orthotopic liver transplantation (OLT). Fourteen consecutive liver transplant candidates (11 male, 3 female) were prospectively enrolled into the study. A 4F aortic catheter with an integrated fiber‐optic device and a thermistor was inserted via a femoral artery sheath for invasive aortic (INV) PDRICG assessment in all patients. The fiber‐optic device was connected to a computer system (COLD‐Z021, PULSION Medical Systems, Munich, Germany). A finger‐piece sensor was used for non‐invasive (NINV) pulse‐densitometric PDRICG assessment. For the PDRICG assessment .5 mg/kg of ICG in cooled saline (10‐15 mL) was injected through a central venous catheter. The assessments of PDRICG were performed after induction of anesthesia, after clamping of the hepatic artery, after clamping of the inferior vena cava, after reperfusion of the graft, and on the first postoperative day. During the PDRICG measurements, the investigators were blinded for the results of the noninvasive monitoring. Seventy‐one pairs of measurements were performed successfully. PDRICG ranged from 0%/min to 43.8 %/min (11.6%/min ± 9.6 %/min, mean ± SD) for invasive and from 2.6%/min to 36.1 %/min (10%/min ± 7.6 %/min, mean ± SD) for noninvasive assessment method. The linear regression analysis yielded the equation: PDRICGNINV = 1.493 ± 0.735 × PDRICGINV, with a correlation coefficient of r = 0.93 (P < .0001). The analysis according to Bland and Altman showed a good agreement between the PDRICGNINV and PDRICGINV with a mean bias 1.5 ± 3.8 for all measurements. In conclusion, according to these results, the noninvasive transcutaneous pulse‐densitometric method correlates well with the invasive aortic fiber‐optic method and thus can be used in patients undergoing liver transplantation. (Liver Transpl 2004;10:1060–1064.)

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.

Extracorporeal albumin dialysis in patients with Amanita phalloides poisoning

Background: Ingestion of Amanita phalloides is the most common cause of lethal mushroom poisoning. The relative late onset of symptoms is a distinct diagnostic feature of Amanita intoxication and also the main reason of failure for extracorporeal removal of Amanita‐specific toxins from the gut and circulation.

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.

Current approach to intraoperative monitoring in liver transplantation.

Purpose of reviewAlthough liver transplantation has become a standardized treatment and the only established definite therapy for end-stage liver disease it remains a unique clinical procedure. Increased understanding of the specific pathophysiological changes in end-stage liver disease and the transplantation procedure have led to the adaptation of concepts including overall monitoring of the patient and assessment of specific organ function. Recent findingsMajor emphasis is placed on adequate monitoring during perioperative care of liver transplantation patients in order to ensure optimal hemodynamic and respiratory performance. The immediate assessment of metabolism and graft function will also serve to guide therapy according to the individual patients needs. SummaryThe evolution of monitoring during standardized liver transplantation, as well as currently recommended novel devices and concepts, are described and discussed.

Liver support in fulminant liver failure after hemorrhagic shock.

ZusammenfassungFulminantes Leberversagen stellt eine interdis ziplinäre medizinische Herausforderung dar. Trotz den Verbesserungen in der Intensivmedizin bleibt die Mortalität mit bis zu 80% aufgrund der Komplikationen wie Hirnödem, Sepsis und Multiorganversagen hoch. Die einzige kurative Therapie für Patienten mit fulminantem Leberversagen, bei denen eine spontane Regeneration nicht möglich ist, stellt die Lebertransplantation dar. Dies ist aber mangels Spenderorganen und der kritischen Gesamtsituation des Patienten nicht immer möglich.Maschinelle Leberunterstützungsverfahren könnten es ermöglichen, die Zeit bis zur Lebertransplantation oder bis zur Erholung der erkrankten Leber zu überbrücken. Prinzipiell unterscheidet man verschiedene Detoxifikationsverfahren und zellgestützte Bioreaktoren. Einer von den neueren extrakorporalen Detoxifikationssystemen ist das Molecular Adsorbent Recirculating System (MARS). MARS funktioniert auf Basis der Albumindialyse und entfernt albumingebundene und wasserlösliche Toxine aus dem Patientenblut.Wir berichten über einen jungen Patienten, der sich mit den typischen Symptomen einer ischämischen Hepatitis und konsekutivem Multiorganversagen (APACHE II Score 38→ vorhergesagte Mortalität 87%) nach einem prolognierten hämorrhagischen Schock präsentierte. Eine Lebertransplantation war wegen der Anamnese von Metastasen eines Insulinoms kontraindiziert. Aggressive konservative Therapie und extrakorporale Leberunterstützungstherapie mit MARS war die einzige gegebene Möglichkeit, um das kritische Zustandsbild zu stabilisieren.Wir haben den Patienten 5 Zyklen der MARS Therapie unterzogen. Während der MARS-Therapie haben wir eine deutliche Verbesserung der Hämodynamik, der Lungenfunktion, des Säure-Basen-Haushaltes und der Laborparametern registriert. Die Plasmaverschwinderate von Indocyaningrün, ein dynamischer Leberfunktionsparameter, hat sich ebenfalls verbessert. Obwohl ein ausgeprägtes Hirnödem im CT mit hochgradig eingeschränktem Blutfluss im transkraniellen Ultraschall diagnoszitiert wurden, hat sich der Patient auch neurologisch völlig erholt. Der Patient hat überlebt und konnte aus dem Spital ohne Folgeschäden entlassen werden. Durch MARS-Therapie konnte die kritischste Periode des Leberversagens bis zur Regeneration erfolgreich überbrückt werden.SummaryAcute liver failure (ALF) is a rare clinical syndrome associated with a mortality of up to 80% and its management remains an interdisciplinary challenge. Despite recent improvements in intensive care management, the mortality of patients with ALF remains high and is related to complications such as cerebral edema, sepsis and multiple organ failure. Emergency orthotopic liver transplantation (OLT) is currently the only effective treatment for those patients who are unlikely to recover spontaneously. Nevertheless, OLT is not always possible because of the shortage of the organs and/or complications related to ALF.Newly introduced liver-assist devices can temporarily support the patient’s liver until native liver recovers or can serve as a bridging device until a liver graft is available. The support devices use both cell-based and non-cell-based techniques. One of the latest non-cell-based extracorporeal hepatic support devices, the molecular adsorbent recycling system (MARS), is based on the concept of albumin dialysis. MARS utilises selective hemodiafiltration with countercurrent albumin dialysis aiming to selectively remove both water-soluble and albumin-bound toxins of the low and middle molecular-weight range.We report on a young patient who presented with clinical symptoms of ischemic hepatitis and multi-organ failure (APACHE II score 38→ predicted postoperative mortality 87%) due to prolonged hemorrhagic shock. OLT was contraindicated because of history of pancreas cancer with metastases. It was necessary to use aggressive conservative therapy and an extracorporeal liver-assist device until liver regeneration began and hemodynamic conditions were stable.The patient underwent five treatments with MARS. During the treatment, there were improvements of hemodynamics, respiratory function, acid-base disturbances and laboratory parameters. The plasma disappearance rate of indocyanine green, a parameter of dynamic liver function, improved during MARS treatment. Although repeated neurological examination predicted diffuse brain damage (brain oedema, decreased cerebral blood flow), the patient recovered without any neurological deficits. The patient survived and was discharged from the hospital in good condition. In this case MARS treatment was successful in supporting the patient through the most critical period of ALF.

Macrophage migration inhibitory factor as a potential predictor for requirement of renal replacement therapy after orthotopic liver transplantation

Acute kidney injury (AKI) after orthotopic liver transplantation (OLT) is associated with a poor clinical outcome. Because there is no specific treatment for postoperative AKI, early recognition and prevention are fundamental therapeutic approaches. Concentrations of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) are elevated in patients with kidney disease. We hypothesized that plasma MIF concentrations would be greater in patients developing AKI after OLT compared with patients with normal kidney function. Twenty‐eight patients undergoing OLT were included in the study. Kidney injury was classified according to AKI network criteria. Fifteen patients (54%) developed severe AKI after OLT, 11 (39%) requiring renal replacement therapy (RRT). On the first postoperative day, patients with severe AKI had greater plasma MIF concentrations (237 ± 123 ng/mL) than patients without AKI (95 ± 63 ng/mL; P < 0.001). The area under the receiver operating characteristic (ROC) curve for predicting severe AKI was 0.87 [95% confidence interval (CI), 0.69‐0.97] for plasma MIF, 0.61 (95% CI, 0.40‐0.79) for serum creatinine (sCr), and 0.90 (95% CI, 0.72‐0.98) for delta serum creatinine (ΔsCr). Plasma MIF (P = 0.02) and ΔsCr (P = 0.01) yielded a better predictive value than sCr for the development of severe AKI. Furthermore, the area under the ROC curve to predict the requirement of RRT was 0.87 (95% CI, 0.68‐0.96) for plasma MIF, 0.65 (95% CI, 0.44‐0.82) for sCr, and 0.72 (95% CI, 0.52‐0.88) for ΔsCr. Plasma MIF had a better predictive value than sCr for the requirement of RRT (P = 0.02). In conclusion, postoperative plasma MIF concentrations were elevated in patients who developed severe AKI after OLT. Furthermore, plasma MIF concentrations showed a good prognostic value for identifying patients developing severe AKI or requiring postoperative RRT after OLT. Liver Transpl 21:662–669, 2015.

Lipocalin-2 Serum Levels Are Increased in Acute Hepatic Failure

Lipocalin-2 (LCN-2), which is expressed in immunocytes as well as hepatocytes, is upregulated in cells under stress from infection or inflammation with increase in serum levels. We sought to investigate the relevance of LCN-2 in the setting of acute hepatic failure, particularly when addressed with the molecular adsorbent recirculating system (MARS). We measured serum LCN-2 concentrations with enzyme-linked immunosorbent assay (ELISA) in 8 patients with acute-on-chronic-liver failure (ACLF) and acute liver failure (ALF) who were treated with MARS. The controls were 14 patients with stable chronic hepatic failure (CHF). LCN-2 was determined immediately before and after the first MARS session. Baseline LCN-2 serum concentrations were significantly increased among ACLF and ALF patients as compared with CHF (P = .004 and P = .0086, respectively). There was no significant difference between the ALF and ACLF group. Moreover, serum LCN-2 levels did not change significantly during the MARS treatment. Serum LCN-2 levels, therefore, may be useful to discern acute from chronic hepatic failure and to monitor the course as well as the severity of the disease.