Daniel Seehofer

Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: A controlled trial in liver transplant recipients

Background. Early enteral nutrition with solutions containing prebiotics (fiber) and probiotics (Lactobacillus) is suggested to reduce bacterial translocation and minimize the incidence of infections after liver transplantation. Methods. In a prospective, randomized placebo-controlled trial consisting of 95 patients, we compared the incidence of postoperative infections and other complications after liver transplantation among three different groups, all supplied with early enteral nutrition: (a) standard formula plus selective bowel decontamination (SBD), (b) fiber-containing formula plus living Lactobacillus plantarum 299, and (c) fiber-containing formula plus heat-killed L plantarum 299. Results. The groups were comparable regarding preoperative American Society of Anesthesiologists classification, Child-Pugh classification of cirrhosis, operative data, and degree of immunosuppression. The patients who received living lactobacilli plus fiber developed significantly fewer bacterial infections (13%) than the patients with SBD (48%). The incidence of infections was 34% in the group with inactivated lactobacilli and fiber. Cholangitis and pneumonia were the leading infections and enterococci the most commonly isolated bacteria. In the living Lactobacillus group, the mean duration of antibiotic therapy, the mean total hospital stay, and the stay on the intensive care unit were also shorter than in the groups with inactivated lactobacilli and fiber as well as with SBD. However, these differences did not reach statistical significance. Conclusions. Early enteral nutrition with fiber-containing solutions and living L plantarum 299 was well tolerated. It decreases markedly the rate of postoperative infections both in comparison with inactivated L plantarum 299 and significantly with SBD and a standard enteral nutrition formula. As it is a cheap and feasible alternative to SBD, further studies should evaluate whether this ecoimmunonutrition should be already started while patients are on the waiting list for transplantation.

Supply of Pre- and Probiotics Reduces Bacterial Infection Rates After Liver Transplantation—A Randomized, Double-Blind Trial

Bacterial infections frequently occur early after liver transplantation. We recently reported significant progress with a synbiotic composition, consisting of one lactic acid bacteria (LAB) and one fiber, which reduced the infection rate from 48% (with selective bowel decontamination) to 13%. Now, our aim is to study if a combination of different LAB and fibers would further improve outcome.

Early enteral supply of fiber and Lactobacilli versus conventional nutrition: a controlled trial in patients with major abdominal surgery

OBJECTIVE Early enteral nutrition with fiber-containing solutions plus Lactobacillus may reduce bacterial translocation and minimize the incidence of infections after surgery. METHODS In a prospective, randomized trial in three groups (n = 30/group) of patients after major abdominal surgery, we compared our previous regimen with parenteral nutrition or fiber-free enteral nutrition (group A) with enteral fiber-containing nutrition with living Lactobacillus (group B) and heat-killed Lactobacillus (group C). The main endpoint was the development of bacterial infection. Other analyzed parameters were the durations of antibiotic therapy and hospital stay, non-infectious complications, side effects of the nutrition, and onset of bowel movement. Routine parameters, nutritional parameters, and cellular immune status in the blood were measured preoperatively and on 1, 5, and 10 d postoperatively. RESULTS The incidence of infections was significantly lower (P = 0.01) in groups B and C with enteral nutrition containing fibers (10% each) than in group A (30%). Patients in group B received antibiotics for a significantly shorter time (P = 0.04) than did the patients in groups A and C. The length of hospital stay and the incidence of non-infectious complications did not differ significantly. Fibers and lactobacilli were well tolerated. There were no general benefits of living Lactobacillus as opposed to heat-killed Lactobacillus in the entire study population, but benefits were observed in the patients with gastric and pancreas resections, although no statistical analysis was done due to their small numbers. CONCLUSIONS Early enteral nutrition with fiber-containing solutions reduced the rate of postoperative infections in comparison with parenteral nutrition and fiber-free enteral formula. Addition of living Lactobacillus seemed to increase the benefits in patients with gastric and pancreatic resections.

Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic liver disease

The relevance of sobriety for outcome after orthotopic liver transplantation (OLT) for alcoholic liver disease (ALD) is still discussed controversially. We conducted a retrospective analysis of 300 patients transplanted for ALD with regard to recurrent alcohol consumption, risk factors for drinking after OLT, and long‐term survival. The 300 patients underwent OLT for ALD between 1989 and 2002. Median follow‐up was 89 months. Incidence and severity of drinking, survival rates, and causes of death were assessed. Age, gender, duration of pretransplant sobriety, social support, presence of children, and the results of psychosomatic evaluation were analyzed for their impact on recurrent alcohol consumption after OLT. Drinking of various degrees was observed in 19% of ALD patients after OLT. Pretransplant sobriety of less than 6 months, absence of companion in life, presence of young children, and a predicted poor psychosomatic prognosis were associated with an increased risk of recurrent alcohol consumption, whereas age and gender were not independent risk factors. Survival rates of patients who resumed abusive drinking were significantly lower than survival rates of abstinent patients or patients with minor lapses. Recurrent alcoholic liver disease accounted for the vast majority of deaths among patients who resumed abusive drinking after OLT, whereas malignant tumors, infections, and cardiovascular disease were the most common causes of death among abstinent patients. In conclusion, abusive drinking after OLT is associated with poor long‐term survival. Analysis of risk factors may help to identify patients with a high risk for recurrent alcohol abuse after OLT. Liver Transpl, 2006.

Effect of Enteral Nutrition and Synbiotics on Bacterial Infection Rates After Pylorus-preserving Pancreatoduodenectomy A Randomized, Double-blind Trial

Objective:Patients undergoing pancreas resection carry several risk factors for nosocomial bacterial infections. Pre- and probiotics (synbiotics) are potentially useful for prevention of these infections. Summary Background Data:First trials in patients following major abdominal surgery including liver transplantation using one Lactobacillus (LAB) and one fiber showed significant reduction of infection rates and reduced length of antibiotic therapy compared with a control group. The present study was designed to analyze whether a combination of different LAB and fibers would further improve outcome. Methods:A prospective randomized monocentric double-blind trial was undertaken in 80 patients following pylorus-preserving pancreatoduodenectomy (PPPD). All patients received enteral nutrition immediately postoperatively. One group (A) received a composition of 4 LAB and 4 fibers, and another group (B) received placebo (fibers only) starting the day before surgery and continuing for 8 days. Thirty-day infection rate, length of hospital stay, duration of antibiotic therapy, noninfectious complications, and side effects were recorded. Results:The incidence of postoperative bacterial infections was significantly lower with LAB and fibers (12.5%) than with fibers only (40%). In addition, the duration of antibiotic therapy was significantly shorter in the latter group. Fibers and LAB were well tolerated. Conclusion:Early enteral nutrition supplemented with a mixture of LAB and fibers reduces bacterial infection rates and antibiotic therapy following PPPD.

Biliary Complications After Liver Transplantation: Old Problems and New Challenges

Due to a vulnerable blood supply of the bile ducts, biliary complications are a major source of morbidity after liver transplantation (LT). Manifestation is either seen at the anastomotic region or at multiple locations of the donor biliary system, termed as nonanastomotic biliary strictures. Major risk factors include old donor age, marginal grafts and prolonged ischemia time. Moreover, partial LT or living donor liver transplantation (LDLT) and donation after cardiac death (DCD) bear a markedly higher risk of biliary complications. Especially accumulation of several risk factors is critical and should be avoided. Prophylaxis is still a major issue; however no gold standard is established so far, since many risk factors cannot be influenced directly. The diagnostic workup is mostly started with noninvasive imaging studies namely MRI and MRCP, but direct cholangiography still remains the gold standard. Especially nonanastomotic strictures require a multidisciplinary treatment approach. The primary management of anastomotic strictures is mainly interventional. However, surgical revision is finally indicated in a significant number of cases. Using adequate treatment algorithms, a very high success rate can be achieved in anastomotic complications, but in nonanastomotic strictures a relevant number of graft failures are still inevitable.

Preoperative antiviral treatment and postoperative prophylaxis in HBV-DNA positive patients undergoing liver transplantation.

BACKGROUND Despite passive immunoprophylaxis a significant number of patients, especially if hepatitis B virus (HBV) DNA is positive prior to transplantation, develop HBV recurrence. This number might be reduced by lowering viral replication pretransplant with antiviral agents and by postoperative combination of antiviral agents and passive immunoprophylaxis. PATIENTS AND METHODS A total of 74 HBV-DNA positive patients who underwent liver transplantation between 9/88 and 4/00 were analyzed retrospectively. Before lamivudine or famciclovir were available, in total 40 patients did not receive any preoperative antiviral therapy. Since 11/93, 17 patients were treated with famciclovir 1500 mg daily, after 4/96 17 patients with lamivudine 150 mg daily prior liver transplantation. Posttransplant all patients received passive immunoprophylaxis aiming at a titer of more than 100 U/liter. In the 34 patients with preoperative antiviral therapy an additional prophylaxis with the respective antiviral agent was applied. RESULTS Under preoperative famciclovir and lamivudine 30 and 71% of patients became HBV-DNA negative, respectively. Actuarial reinfection rate 2 years after liver transplantation was 48% without antiviral prophylaxis, which was not statistically different from 55% under perioperative famciclovir therapy. In contrast only 18% developed HBV recurrence under perioperative lamivudine treatment. During both antiviral regimens neither pre nor posttransplant severe side effects were observed. CONCLUSION Perioperative application of famciclovir is not recommendable, whereas lamivudine seems to lower recurrence rates significantly. Whether the observed effect is due to pre- or postoperative application remains to be addressed in further studies. In addition the long-term course has to be awaited.

Effectiveness of triclosan-coated PDS Plus versus uncoated PDS II sutures for prevention of surgical site infection after abdominal wall closure: the randomised controlled PROUD trial

BACKGROUND Postoperative surgical site infections are one of the most frequent complications after open abdominal surgery, and triclosan-coated sutures were developed to reduce their occurrence. The aim of the PROUD trial was to obtain reliable data for the effectiveness of triclosan-coated PDS Plus sutures for abdominal wall closure, compared with non-coated PDS II sutures, in the prevention of surgical site infections. METHODS This multicentre, randomised controlled group-sequential superiority trial was done in 24 German hospitals. Adult patients (aged ≥18 years) who underwent elective midline abdominal laparotomy for any reason were eligible for inclusion. Exclusion criteria were impaired mental state, language problems, and participation in another intervention trial that interfered with the intervention or outcome of this trial. A central web-based randomisation tool was used to randomly assign eligible participants by permuted block randomisation with a 1:1 allocation ratio and block size 4 before mass closure to either triclosan-coated sutures (PDS Plus) or uncoated sutures (PDS II) for abdominal fascia closure. The primary endpoint was the occurrence of superficial or deep surgical site infection according to the Centers for Disease Control and Prevention criteria within 30 days after the operation. Patients, surgeons, and the outcome assessors were masked to group assignment. Interim and final analyses were by modified intention to treat. This trial is registered with the German Clinical Trials Register, number DRKS00000390. FINDINGS Between April 7, 2010, and Oct 19, 2012, 1224 patients were randomly assigned to intervention groups (607 to PDS Plus, and 617 to PDS II), of whom 1185 (587 PDS Plus and 598 PDS II) were analysed by intention to treat. The study groups were well balanced in terms of patient and procedure characteristics. The occurrence of surgical site infections did not differ between the PDS Plus group (87 [14·8%] of 587) and the PDS II group (96 [16·1%] of 598; OR 0·91, 95% CI 0·66-1·25; p=0·64). Serious adverse events also did not differ between the groups-146 of 583 (25·0%) patients treated with PDS Plus had at least one serious adverse event, compared with 138 of 602 (22·9%) patients treated with PDS II; p=0·39). INTERPRETATION Triclosan-coated PDS Plus did not reduce the occurrence of surgical site infection after elective midline laparotomy. Innovative, multifactorial strategies need to be developed and assessed in future trials to reduce surgical site infections. FUNDING Johnson & Johnson Medical Limited.

Twenty‐Year Longitudinal Follow‐Up After Orthotopic Liver Transplantation: A Single‐Center Experience of 313 Consecutive Cases

With excellent short‐term survival in liver transplantation (LT), we now focus on long‐term outcome and report the first European single‐center 20‐year survival data. Three hundred thirty‐seven LT were performed in 313 patients (09/88–12/92). Impact on long‐term outcome was studied and a comparison to life expectancy of matched normal population was performed. A detailed analysis of 20‐years follow‐up concerning overweight (HBMI), hypertension (HTN), diabetes (HGL), hyperlipidemia (HLIP) and moderately or severely impaired renal function (MIRF, SIRF) is presented. Patient and graft survival at 1, 10, 20 years were 88.4%, 72.7%, 52.5% and 83.7%, 64.7% and 46.6%, respectively. Excluding 1‐year mortality, survival in the elderly LT recipients was similar to normal population. Primary indication (p < 0.001), age (p < 0.001), gender (p = 0.017), impaired renal function at 6 months (p < 0.001) and retransplantation (p = 0.034) had significant impact on patient survival. Recurrent disease (21.3%), infection (20.6%) and de novo malignancy (19.9%) were the most common causes of death. Prevalence of HTN (57.3–85.2%, p < 0.001), MIRF (41.8–55.2%, p = 0.01) and HBMI (33.2–45%, p = 0.014) increased throughout follow‐up, while prevalence of HLIP (78.0–47.6%, p < 0.001) declined. LT has conquered many barriers to achieve these outstanding long‐term results. However, much work is needed to combat recurrent disease and side effects of immunosuppression (IS).

Multilineage communication regulates human liver bud development from pluripotency

Conventional two-dimensional differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. Three-dimensional organoids generate complex organ-like tissues; however, it is unclear how heterotypic interactions affect lineage identity. Here we use single-cell RNA sequencing to reconstruct hepatocyte-like lineage progression from pluripotency in two-dimensional culture. We then derive three-dimensional liver bud organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during liver bud development. We find that liver bud hepatoblasts diverge from the two-dimensional lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark three-dimensional liver buds against fetal and adult human liver single-cell RNA sequencing data, and find a striking correspondence between the three-dimensional liver bud and fetal liver cells. We use a receptor–ligand pairing analysis and a high-throughput inhibitor assay to interrogate signalling in liver buds, and show that vascular endothelial growth factor (VEGF) crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.