Auxiliary liver transplantation in acute liver failure in the rat – an illustrated description of a new surgical approach

INTRODUCTION: To investigate auxiliary liver transplantation successfully in rats suffering from acute liver failure, we developed a new surgical approach. METHODS: A 70% hepatectomized liver graft was implanted into the right upper quadrant of the abdomen. The donor portal vein was anastomosed with the recipient's right renal artery using the splint technique. The donor infrahepatic vena cava was attached onto the recipient vena cava end to side. The bile duct was implanted into the duodenum.     

Histidine–tryptophan–ketoglutarate solution for organ preservation in human liver transplantation—a prospective multi-centre observation study

Based on experimental work and clinical small studies, histidine–tryptophan–ketoglutarate (HTK) solution was found to be suitable not only for heart and kidney preservation but also for liver preservation. We decided, therefore, to use this preservation solution for clinical liver preservation in a prospective multi-centre trial. Enrolment to the study was from 1996 to 1999 in four European centres, and the results of 214 patients with HTK-preserved organs were analysed. Analysis showed a primary dysfunction (PDF) rate of 8.8%, with a primary non-function (PNF) rate of 2.3% and initial poor function (IPF) in 6.5%. Patient survival rate at 1 year was 83% and 1-year graft survival rate was 80%. In a univariate and a multivariate analysis PDF, early surgical complications and tendentiously severe infections (septicaemia, pneumonia, cholangitis) were identified as independent risk factors for graft and patient survival. Preservation with HTK can be regarded as an established alternative to preservation with University of Wisconsin (UW) solution when preservation times are short. Definitive assessment of the efficacy of preservation solutions requires further prospective randomised clinical trials that compare HTK and UW.     

Probiotics partly reverse increased bacterial translocation after simultaneous liver resection and colonic anastomosis in rats

BACKGROUND: Bacterial translocation is one important cause of nosocomial infections following major abdominal surgery. Oral administration of probiotics has been proposed to diminish bacterial translocation. MATERIAL AND METHODS: In total 68 rats were divided into seven groups: five of the groups received standard rat chow and were subjected to either sham-operation, 70% liver resection, colonic anastomosis, or a combination of 30 or 70% liver resection with synchronous colonic anastomosis, respectively. In two additional groups with synchronous operation, a combination of four different lactic acid bacteria and four fibers was administered two times daily pre- and postoperatively. Bacterial concentrations in cecum, mesenteric lymph nodes, liver, and spleen were analyzed and blood cultures were taken 48 h after operation. Furthermore, the following parameters were assessed: histological changes in the intestine, intestinal paracellular permeability (Ussing chamber), bursting pressure of the colonic anastomosis, and mitosis rate of the remnant liver. RESULTS: Bacterial translocation was observed in all rats, except in the sham group. Following liver resection, the highest bacterial concentrations were seen in liver and spleen, following colon anastomosis in the mesenteric lymph nodes. Bacterial translocation was increased in the animals with combined operation, in parallel to the extent of liver resection. In rats with colon anastomosis, bacterial concentration in the cecum was also higher than in the sham group. Application of probiotics significantly decreased bacterial concentration in the lymph nodes. In addition, animals with a high cecal concentration of lactobacilli had less translocation than the others. No histological changes were observed in the intestine. Paracellular permeability for ions, but not for the larger molecule lactulose, was increased in the colon in all groups with colon anastomosis. The bursting pressure of the colon anastomosis was not significantly different between the groups. Seventy percent liver resection led to a high rate of hepatocyte mitosis, whereas combination with colon anastomosis impaired the regeneration process. CONCLUSION: Synchronous liver resection and colon anastomosis led to increased bacterial translocation compared to the single operations in the rat model. It is possible to diminish this process by oral administration of probiotics. Bacterial overgrowth in the cecum and impaired hepatic regeneration, but not histological changes or alterations of paracellular permeability, are potential pathogenic mechanisms for translocation in this setting.     

Comparative analysis of procoagulatory activity of haemodialysis, haemofiltration and haemodiafiltration with a polysulfone membrane (APS) and with different modes of enoxaparin anticoagulation.

BACKGROUND: Treatment modalities of renal replacement therapy differ in their diffusive and convective mass transfer characteristics. It was the goal of this study to clarify whether an increase in convective mass transfer as performed with haemofiltration (HF) and haemodiafiltration (HDF) in comparison with high-flux haemodialysis (HD) is associated with an alteration in procoagulatory activity or with complement activation. METHODS: Ten stable chronic HD patients were monitored during 120 treatments in a randomized cross over design. A high-flux polysulfone dialyser (APS 900) was used for high-flux HD, pre-dilution HF and pre-dilution HDF. Constant flow of on-line substitution fluid for HF and HDF was 200 ml/min. The low molecular weight heparin (LMWH) enoxaparin was used for anticoagulation (i) as single bolus (50 IU/kg body weight, median 3700 IU) and (ii) as bolus of 1200 IU followed by a median continuous dose of 400 IU/h. Blood samples were collected before the LMWH bolus, after 10 min, 60 min, 120 min and at the end of treatment in venous and arterial blood lines to determine antiXa activity, thrombin-antithrombin-III complex (TAT), D-dimer and C5a generation. RESULTS: Net ultrafiltration did not significantly differ between HD, HF and HDF but total ultrafiltration in HF and HDF far exceeded total ultrafiltration in HD. With conditions of single bolus, or bolus and continuous anticoagulation with enoxaparin, after comparable treatment times (median duration 4.25 h), TAT and D-dimer generation at identical anti-Xa levels revealed significantly higher coagulation activity during HF and HDF, compared with high-flux HD as assessed by comparative area under the curve (AUC) analysis. Plasma concentration of C5a in venous bloodlines did not significantly differ during HD, HF and HDF. CONCLUSION: A higher convective mass transfer during HF and HDF, in comparison with high-flux HD caused by a greater total ultrafiltration volume was associated with increased procoagulatory activity in the extracorporeal circuit. Molecular markers assessing the activation of coagulation are appropriate to adjust the anticoagulation regime to high UF volumes in order to minimize bleeding risk and optimize patency of the extracorporeal circuit.     

High‐sensitive Troponin T measurements early after heart transplantation predict short‐ and long‐term survival

Following heart transplantation, cardiac biomarkers remain elevated for several weeks eventually as a result of membrane leakage of the donor organ. We now test the predictive power of blood levels of troponin T (TNT) measured by the new hsTNT assay (Roche Diagnostics, Roche Diagnostics, Mannheim, Germany) early after heart transplantation. TNT was determined in 141 cardiac allograft recipients and 40 controls. Our findings demonstrate that patients who died within the first year after transplantation had significantly higher median hsTNT serum levels 6 weeks after transplantation (156 ng/l ± 203 vs. 29 ng/l ± 21, P = 0.0002). Using ROC analysis, a serum hsTNT concentration of 33.55 ng/l 6 weeks after transplantation was found to be the best cutoff to predict death at 1 year (HR 0.16, 95%CI:0.05–0.46, P = 0.001) with a sensitivity of 90.91% and a specificity of 70.97%. In addition, survival at 5 years (HR 0.15, 95% CI 0.06–0.35, P < 0.0001) was significantly better among patients below that cutoff value. In multivariate analysis, hsTNT serum level 6 weeks after transplantation emerged as an independent predictor for first‐year mortality (hsTNT–HR 0.90, 95% CI: 0.81–1.00, P = 0.03). Cardiac troponin T concentrations early after transplantation as measured with a highly sensitive assay represent a strong and independent risk predictor of death after heart transplantation.     

Proteomics and transcriptomics of peripheral nerve tissue and cells unravel new aspects of the human Schwann cell repair phenotype

The remarkable feature of Schwann cells (SCs) to transform into a repair phenotype turned the spotlight on this powerful cell type. SCs provide the regenerative environment for axonal re‐growth after peripheral nerve injury (PNI) and play a vital role in differentiation of neuroblastic tumors into a benign subtype of neuroblastoma, a tumor originating from neural crest‐derived neuroblasts. Hence, understanding their mode‐of‐action is of utmost interest for new approaches in regenerative medicine, but also for neuroblastoma therapy. However, literature on human SCs is scarce and it is unknown to which extent human SC cultures reflect the SC repair phenotype developing after PNI in patients. We performed high‐resolution proteome profiling and RNA‐sequencing on highly enriched human SC and fibroblast cultures, control and ex vivo degenerated nerve explants to identify novel molecules and functional processes active in repair SCs. In fact, we found cultured SCs and degenerated nerves to share a similar repair SC‐associated expression signature, including the upregulation of JUN, as well as two prominent functions, i.e., myelin debris clearance and antigen presentation via MHCII. In addition to myelin degradation, cultured SCs were capable of actively taking up cell‐extrinsic components in functional phagocytosis and co‐cultivation assays. Moreover, in cultured SCs and degenerated nerve tissue MHCII was upregulated at the cellular level along with high expression of chemoattractants and co‐inhibitory rather than ‐stimulatory molecules. These results demonstrate human SC cultures to execute an inherent program of nerve repair and support two novel repair SC functions, debris clearance via phagocytosis‐related mechanisms and type II immune‐regulation. GLIA 2016;64:2133–2153     

The multiply injured child

The treatment of multiple traumas in children requires knowledge of common injury patterns, incidence, mortality, and the consequences and differences between these injuries in children and adult patients. However, epidemiological studies concerning pediatric multiple trauma are rare. To address this, data were collected and analyzed from 682 multiple trauma patients treated at a Level I trauma center. The patients were divided into four age-related groups (< 6 years, 6-12 years, 13-18 years, and 18-40 years) and were evaluated for trauma mechanism, injury distribution, and cause of death. Children aged 6 to 17 years mostly were injured as pedestrians and cyclists whereas infants, preschoolers, and adults more commonly were injured as car passengers. Pediatric patients suffered a significantly higher mortality than adults, with a threefold increased risk of death when injured as passengers in car accidents. Injuries to the head and the legs were most common. A lower incidence of thoracic (28% versus. 62%), abdominal (20% versus 36%), pelvic (22% versus 35%), and upper limb (32% versus 43%) trauma was observed in children (< 18 years) than in adults (18-40 years). Nevertheless, trauma to the thorax, abdomen, and head were associated with a high risk of death in all groups. Spinal cord injuries, especially in the cervical region, also carried a high risk of mortality (36.8 in the group of patients younger than 18 years and 18.9 in the group of patients 18-40 years). Children younger than 6 years had the most severe head injuries. The data show that there are important differences in incidence, mortality, and injury patterns between pediatric and adult patients with multiple traumas.     

Effectivity of a T-cell-adapted induction therapy with anti-thymocyte globulin (Sangstat).

BACKGROUND: Cytolytic induction therapy with anti-thymocyte globulin (ATG) should induce effective immunosuppression, with a low rate of rejection in the initial phase after heart transplantation. Induction therapy with ATG allows post-operative renal recovery without the negative effects of highly nephrotoxic cyclosporine levels. An increased rate of infection is a common problem, however, and has been associated with "over-immunosuppression" early after transplantation. Therefore, we investigated whether reduced T-cell-adapted ATG induction therapy could be performed without increasing the risk of graft loss by rejection and whether reductions in infection rates and costs are possible. METHODS: Between March 1999 and December 2002, T-cell-adapted ATG induction therapy with ATG (Sangstat) (1.5 mg/kg) was given to 62 heart transplant recipients (study group) starting on post-operative Days 1 to 6. T-lymphocyte sub-populations were screened daily using flow cytometry. If total lymphocytes were <100/microl (reference 1,300 to 2,300/microl), T-helper lymphocytes (CD4+) <50/microl (reference >500/microl) and T-suppressor cells (CD8+) <50/microl (reference >300/microl), then no ATG was given. Further immunosuppression was continued with triple therapy consisting of methylprednisolone, azathioprine and cyclosporine. An historic group of heart transplant recipients given a full-dose ATG regimen for 8 days served as controls. These recipients were treated with ATG (Merieux 1.5 mg/kg) until reaching monoclonal cyclosporine levels of >300 mg/dl. Additional immunosuppressive treatment did not differ. Patients in both groups received systemic antibiotics (Imipenem) peri-operatively. Results of routine endomyocardial biopsies and rates of infections were examined. RESULTS: Study group patients were older (52 +/- 10 vs 49 +/- 14 years). In the study group, mean cumulative ATG dose was reduced significantly to 596 +/- 220 mg (p < 0.05) for 3.9 +/- 1.6 days compared with 1,159 +/- 376 mg for 6.9 +/- 1.1 days in the control group. The rate of cytomegalovirus (CMV) seroconversion was 23% in the study group compared with 13% in the control group. Rate of deep sternal infections was lower in the study group (1.6% vs 3.2%). The mean rejection rate in the first 3 months was 0.4 +/- 0.7 for the study patients (185 biopsies) vs 1.1 +/- 1.7 for controls (237 biopsies). All biopsies with ISHLT Grade >2 were treated successfully with 1,000 mg of methylprednisolone intravenously for 3 days. Both groups showed a similar 1-year survival rate (study 88%, control 89%). CONCLUSIONS: T-cell-adapted ATG induction therapy can be a helpful tool for individualized immunosuppression. It is not associated with an increased rate of rejection. Lower doses of immunosuppression help to minimize the rates of infection. In addition, cytolytic induction therapy combined with reduced ATG results in significant cost reduction.     

Effects of short-term propofol administration on pancreatic enzymes and triglyceride levels in children

This prospective, clinical trial evaluated the effects of short-term propofol administration on triglyceride levels and serum pancreatic enzymes in children undergoing sedation for magnetic resonance imaging. Laboratory parameters of 40 children, mean age (SD; range) 67 (66; 4-178) months undergoing short-term sedation were assessed before and 4 h after having received propofol. Mean (SD) propofol loading dose was 2.2 (1.1) mg.kg(-1) followed by continuous propofol infusion of 6.9 (0.9) mg.kg(-1).h(-1). Serum lipase levels (p = 0.035) and serum triglyceride levels (p = 0.003) were raised significantly after propofol administration but remained within normal limits. No significant changes in serum pancreatic-amylase levels were seen (p = 0.127). In two (5%) children, pancreatic enzymes and in four (10%) children triglyceride levels were raised above normal limits; however, no child showed clinical symptoms of pancreatitis. We conclude that even short-term propofol administration with standard doses of propofol may have a significant effect on serum triglyceride and pancreatic enzyme levels in children.