Die Verwendung eines Immunsuppressivums (Tacrolimus) als Rinse-Solution zur Reduktion von Ischämie-Reperfusionsschäden bei der experimentellen Lebertransplantation

Seit Beginn der 1990er Jahre sind protektive Wirkungen von Tacrolimus auf Ischämie-Reperfusionsschäden der Leber bekannt. Die in bisherigen experimentellen Arbeiten beschriebene Spenderpräkonditionierung erscheint jedoch wegen potenzieller Nebenwirkungen klinisch nicht umsetzbar. Eine amerikanische Arbeitsgruppe konnte dabei in einer klinischen Pilot-Studie zeigen, dass die Spülung humaner Lebern mit Tacrolimus (20ng/ml) vor Implantation zu einer signifikanten Reduktion von Ischämie-Reperfusionsschäden nach Lebertransplantation führte. Unsere Arbeitsgruppe hat umfangreiche Untersuchungen mit Glutathion als Therapeutikum von Ischämie-Reperfusionsschäden nach warmer und kalter Ischämie durchgeführt. Gleichzeitig scheint, dass intrazelluläres Glutathion bei Anwesenheit hoher Konzentrationen von ROS über die Induktion von Radikalkettenreaktionen beziehungsweise die Thiolierung anderer Proteine selbst als Mediator von Ischämie-Reperfusionsschäden fungieren kann. In Vorarbeiten untersuchten wir die Wirkung von Tacrolimus im isoliert-perfundierten Modell der Rattenleber. Die Vorbehandlung mit Tacrolimus bewirkte bei Zufuhr von H2O2 eine Verringerung des ROS-induzierten zellulären Schadens, ausgedrückt in einer dosisabhängigen, signifikanten Verringerung des LDH-Efflux. Als Ursache hierfür wird eine verminderte intrazelluläre Akkumulation von zytotoxischem GSSG diskutiert, das nach Tacrolimus-Gabe vermehrt in Galle und Blut freigesetzt wurde, während die Aktivität der an Bildung und Abbau von GSH/GSSG beteiligten Enzyme Katalase, GSH-Peroxidase und GSSG-Reduktase unverändert war. Dieser Effekt konnte durch Gabe des p38 MAPK Inhibitors SB203580 imitiert werden. Wir übertrugen daraufhin das Konzept der Tacrolimus-Rinse in das Modell der arterialisierten, orthotopen Lebertransplantation an der Ratte. Die Spülung der Leber (20ml) mit Tacrolimus unmittelbar vor Implantation in den Empfängerorganismus führte zu einer signifikanten Reduktion des Ischämie-Reperfusionsschadens, gemessen in Transaminasen, LDH sowie Gallefluss. Das höchste Ausmass an Zytoprotektion wurde durch eine Tacrolimus-Konzentration von 10 ng/ml erreicht, wobei die protektive Wirkung der Tacrolimus-Rinse in der 10 ng-Gruppe stärker ausgeprägt war als in der 50 ng-Gruppe. Die Ursachen für diese inverse Dosis-Wirkungsbeziehung sind unklar, zumal keine statistische Signifikanz zwischen den beiden Gruppen besteht. Außerdem fehlen bislang systematische Untersuchungen zur optimalen Tacrolimus-Dosis in dieser Versuchsanordnung. Als Wirkmechanismus der Tacrolimus-Rinse postulieren wir - aufbauend auf Voruntersuchungen im isoliert perfundierten Modell und den erhobenen in-vivo-Daten - Veränderungen der zellulären Glutathionhomöostase: Hepatozyten setzten im Modell der Lebertransplantation nach Tacrolimus-Rinse vermehrt zytotoxisches GSSG in Blut und Galle frei, wodurch ROS-vermittelte Zellschäden während der Reperfusion minimiert werden. Zusammenfassend kann aufgrund der bisherigen Untersuchungen gezeigt werden, dass die Tacrolimus-Rinse eine neue und klinisch praktikable Therapieoption von Ischämie-Reperfusionsschäden der Leber darstellen könnte

Assessing Non-Invasive Liver Function in Patients With Intestinal Failure Receiving Total Parenteral Nutrition-Results From the Prospective PNLiver Trial

Liver abnormalities in intestinal failure (IF) patients receiving parenteral nutrition (PN) can progress undetected by standard laboratory tests to intestinal failure associated liver disease (IFALD). The aim of this longitudinal study is to evaluate the ability of non-invasive liver function tests to assess liver function following the initiation of PN. Twenty adult patients with IF were prospectively included at PN initiation and received scheduled follow-up assessments after 6, 12, and 24 months between 2014 and 2019. Each visit included liver assessment (LiMAx [Liver Maximum Capacity] test, ICG [indocyanine green] test, FibroScan), laboratory tests (standard laboratory test, NAFLD [non-alcoholic fatty liver disease] score, FIB-4 [fibrosis-4] score), nutritional status (bioelectrical impedance analysis, indirect calorimetry), and quality of life assessment. The patients were categorized post-hoc based on their continuous need for PN into a reduced parenteral nutrition (RPN) group and a stable parenteral nutrition (SPN) group. While the SPN group (n = 9) had significantly shorter small bowel length and poorer nutritional status at baseline compared to the RPN group (n = 11), no difference in liver function was observed between the distinct groups. Over time, liver function determined by LiMAx did continuously decrease from baseline to 24 months in the SPN group but remained stable in the RPN group. This decrease in liver function assessed with LiMAx in the SPN group preceded deterioration of all other investigated liver function tests during the study period. Our results suggest that the liver function over time is primarily determined by the degree of intestinal failure. Furthermore, the LiMAx test appeared more sensitive in detecting early changes in liver function in comparison to other liver function tests

Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an "ex vivo" tacrolimus perfusion

Background: Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts. Methods/Design: The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients. Discussion: Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage. Trial register: EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT0156409

The effect of age on short-term and mid-term outcomes after thoracoscopic Ivor Lewis esophagectomy: a propensity score-matched analysis

Background: The number of elderly patients diagnosed with esophageal cancer rises. Current information about outcomes in elderly patients undergoing thoracoscopic Ivor Lewis esophagectomy is limited. The objective of this study was to evaluate the influence of age on short-and mid-term outcomes after thoracoscopic Ivor Lewis esophagectomy. Methods: A retrospective review of 188 patients with esophageal cancer undergoing thoracoscopic Ivor Lewis esophagectomy between August 2014 and July 2019 was performed. Patients were divided into patients aged > 75 years (elderly group (EG), n = 37) and patients = grade III) were compared. Results: After matching 74 patients remained (n = 37 in each group). Postoperatively, no significant differences in major and overall complications, intra-hospital and 30-day mortality, disease-free or overall survival up to 3 years after surgery were noted. The incidence of pulmonary complications (65% vs. 38%) and pneumonia (54% vs. 30%) was significantly higher and the median hospital length of stay (12 vs. 14 days) significantly longer in the EG versus YG. Conclusion: Thoracoscopic Ivor Lewis esophagectomies resulted in acceptable postoperative major morbidity and mortality without compromising 3-years overall and disease-free survival in elderly compared to younger patients with esophageal cancer. However, the incidence of postoperative pulmonary complications was higher in patients aged over 75 years

Robotic-assisted pancreatic surgery in the elderly patient: experiences from a high-volume centre

Background: Robotic-assisted pancreatic surgery (RPS) has fundamentally developed over the past few years. For subgroups, e.g. elderly patients, applicability and safety of RPS still needs to be defined. Given prognosticated demographic developments, we aim to assess the role of RPS based on preoperative, operative and postoperative parameters. Methods: We included 129 patients undergoing RPS at our institution between 2017 and 2020. Eleven patients required conversion to open surgery and were excluded from further analysis. We divided patients into two groups; >= 70 years old (Group 1; n = 32) and < 70 years old (Group 2; n = 86) at time of resection. Results: Most preoperative characteristics were similar in both groups. However, number of patients with previous abdominal surgery was significantly higher in patients >= 70 years old (78% vs 37%, p = 70 years old stayed significantly longer at ICU (1.8 vs 0.9 days; p = 0.037), length of hospital stay and postoperative morbidity were equivalent between the groups. Conclusion: RPS is safe and feasible in elderly patients and shows non-inferiority when compared with younger patients. However, prospectively collected data is needed to define the role of RPS in elderly patients accurately. Trial registration Clinical Trial Register: Deutschen Register Klinischer Studien (DRKS; German Clinical Trials Register). Clinical Registration Number: DRKS00017229 (retrospectively registered, Date of Registration: 2019/07/19, Date of First Enrollment: 2017/10/18)

Pharmacokinetics of tigecycline in critically ill patients with liver failure defined by maximal liver function capacity test (LiMAx)

Background: In critically ill patients, tigecycline (TGC) remains an important therapeutic option due to its efficacy against multiresistant Gram-positive and Gram-negative bacteria. TGC is metabolized and eliminated predominantly by the liver. Critical illness-induced liver failure may have a profound impact on the pharmacokinetic of TGC. In the present study, we aimed to establish a link between the degree of liver dysfunction and TGC plasma concentration using the novel maximum liver function capacity (LiMAx) test, as a dynamic liver function test. Materials/methods: The prospective study included 33 patients from a surgical ICU with the clinical indication for antibiotic therapy with TGC. The patients received 100 mg loading dose of TGC followed by intermittent standard doses of 50 mg q12. Blood samples for TGC plasma concentration were collected at 0.3, 2, 5, 8 and 11.5 h in a steady-state condition after at least 36 h post-standard dosage. The results were analyzed by means of a high-performance liquid chromatography (HPLC) method. Within the same day, the LiMAx test was carried out and routine blood parameters were measured. Results: Peak plasma concentrations of TGC were significantly higher in patients with severe liver failure (LiMAx  300 µg/kg/h). The pharmacokinetic curves revealed higher values in severe liver failure at any measured point. Moreover, LiMAx and total bilirubin were the only liver-related parameters that correlated with TGC Cmax. Conclusions: The present study demonstrates a high variability of TGC plasma concentrations in critically ill patients. The results show a significant correlation between the degree of liver dysfunction, measured by the LiMAx test, and TGC Cmax. LiMAx test may be a helpful tool beyond others for adjusting the required dosage of hepatic metabolized antibiotics in critically ill patients. Trial registry DRKS—German clinical trials register; Trial registration number: DRKS00008888; Date of registration: 07-17-2015; Date of enrolment of the first participant to the trial: 12-10-201

Thoracic Surgery in the COVID-19 Pandemic: A Novel Approach to Reach Guideline Consensus

The COVID-19 pandemic challenges international and national healthcare systems. In the field of thoracic surgery, procedures may be deferred due to mandatory constraints of the access to diagnostics, staff and follow-up facilities. There is a lack of prospective data on the management of benign and malignant thoracic conditions in the pandemic. Therefore, we derived recommendations from 14 thoracic societies to address key questions on the topic of COVID-19 in the field of thoracic surgery. Respective recommendations were extracted and the degree of consensus among different organizations was calculated. A high degree of consensus was found to temporarily suspend non-critical elective procedures or procedures for benign conditions and to prioritize patients with symptomatic or advanced cancer. Prior to hospitalization, patients should be screened for respiratory symptoms indicating possible COVID-19 infection and most societies recommended to screen all patients for COVID-19 prior to admission. There was a weak consensus on the usage of serology tests and CT scans for COVID-19 diagnostics. Nearly all societies suggested to postpone elective procedures in patients with suspected or confirmed COVID-19 and recommended constant reevaluation of these patients. Additionally, we summarized recommendations focusing on precautions in the theater and the management of chest drains. This study provides a novel approach to informed guidance for thoracic surgeons during the COVID-19 pandemic in the absence of scientific evidence-based data