Ex Situ Machine Perfusion of Human Donor Livers via the Surgically Reopened Umbilical Vein:A Proof of Concept

Background. Machine perfusion of donor livers is typically performed via the portal vein main stem. Instead, cannulation of a reopened umbilical vein could allow machine perfusion during organ procurement and subsequent implantation in the recipient without interruption of the portal venous circulation. We aimed to assess the feasibility of portal venous machine perfusion via the umbilical vein. Methods. During back table inspection of 5 human livers declined for transplantation, the umbilical vein was surgically reopened, dilated, and cannulated. Hypothermic and normothermic oxygenated machine perfusion (NMP) were performed using the umbilical vein for portal inflow. Three livers were perfused with hypothermic machine perfusion, 1 full liver graft underwent NMP for 4 hours, and 1 left lateral split procedure was performed under continuous NMP with portal perfusion via the umbilical vein. Results. In all livers, access to the portal venous system via the umbilical vein was successfully achieved with good portal flows and macroscopically homogeneous perfusion. The full liver graft that underwent NMP via the umbilical vein for 4 hours showed good lactate clearance, normalized pH, and achieved good bile production with pH >7.55. During the split procedure under continuous NMP via the umbilical vein, the left lateral segment and extended right lobe remained equally perfused, as demonstrated by Doppler ultrasound. Conclusions. Machine perfusion with portal perfusion via the umbilical vein is feasible. Portal venous flows were similar to those obtained after cannulation of the portal vein main stem. This technique enables continuous oxygenated perfusion of liver grafts during procurement, splitting, and implantation

Donor tobacco smoking is associated with postoperative thrombosis after primary liver transplantation

Background: Thrombosis after liver transplantation is a leading cause of graft loss, morbidity, and mortality. Several known recipient- and surgery-related characteristics have been associated with increased risk of thrombosis after transplantation. Potential donor-related risk factors, however, remain largely undefined. Objectives: We aimed to identify risk factors for early post-transplantation thrombosis ('90 days) and to determine the impact of early postoperative thrombosis on long-term graft and patient survival. Patients/Methods: A post hoc analysis was performed of an observational cohort study including all primary, adult liver transplantations performed between 1993 and 2018. Donor-, recipient-, and surgery-related characteristics were collected. Competing risk model analyses and multivariable regression analyses were performed to identify risk factors for developing early post-transplant thrombosis and graft failure. Results: From a total of 748 adult liver transplantations, 58 recipients (7.8%) developed a thrombosis after a median of 7 days. Post-transplantation thrombotic events included 25 hepatic artery thromboses, 13 portal vein thromboses, and 22 other thrombotic complications. Donor history of smoking was independently associated with early postoperative thrombosis (odds ratio [OR] 2.42; 95% confidence interval [CI], 1.29-4.52). Development of early post-transplant thrombosis was independently associated with patient mortality (hazard ratio [HR] 3.61; 95% CI 1.54-8.46) and graft failure (HR 5.80, 95% CI 3.26-10.33), respectively. Conclusion: Donor history of smoking conveys a more than two-fold increased risk of thrombosis after liver transplantation, independent of other factors. Post-transplant thrombosis was independently associated with decreased patient and graft survival

Utility of preoperative CT-based body metrics in relation to postoperative complications in pediatric liver transplant recipients

BACKGROUND: Computed tomography (CT) derived body metrics such as skeletal muscle index (SMI), psoas muscle index (PMI), and subcutaneous fat index (ScFI) are measurable components of sarcopenia, frailty, and nutrition. While these body metrics are advocated in adults for predicting postoperative outcomes after liver transplantation (LT), little is known about the value in pediatric populations. This study assessed the relation between preoperative CT-based body metrics and postoperative short-term outcomes in pediatric LT recipients. METHODS: Patients aged 0-18 years who underwent a primary LT were retrospectively included (N=101, median age 0.5 years, range 0.2-17.1). SMI, PMI, and ScFI were derived from preoperative axial CT slices. Postoperative outcomes and complications within 90 days were correlated with the CT-based body metrics. To classify postoperative infections, the Clavien-Dindo (CD) classification was used. Subgroup analyses were performed for age groups (10 years old). An optimal threshold for test performance was defined using Youden's J-statistic and receiver operating characteristic curve as appropriate. RESULTS: ScFI was significantly (P=0.001) correlated with moderate to severe postoperative infections (CD grade 3-5) in children <1 year old, with the optimal ScFI threshold being ≤27.1 cm2 /m2 (sensitivity 80.4% and specificity 77.8%). A weak negative correlation between SMI and the total duration of hospital stay (R=-0.33, P=0.010) and intensive care unit stay (R=-0.32, P 0.013) was observed in children <1 year old. No other associations between CT-based body metrics and postoperative outcomes were shown. CONCLUSIONS: In children <1 year old with cirrhotic liver disease undergoing LT, pre-operative CT-based body metrics were correlated with moderate to severe postoperative infections (ScFI), and with longer duration of hospital and ICU stay (SMI), and thus can be considered important tools for pre-LT risk assessment

Evidence for a rebalanced hemostatic system in pediatric liver transplantation:A prospective cohort study

In adults with end-stage liver disease concurrent changes in pro- and antihemostatic pathways result in a rebalanced hemostasis. Children though, have a developing hemostatic system, different disease etiologies, and increased risk of thrombosis. This study aimed to assess the hemostatic state of children during and after liver transplantation. Serial blood samples were obtained from 20 children (≤16 years) undergoing primary liver transplantation (September 2017-October 2018). Routine hemostasis tests, thrombomodulin-modified thrombin generation, clot lysis times, and hemostatic proteins were measured. Reference values were established using an age-matched control group of 30 children. Thrombocytopenia was present in study patients. Von Willebrand factors were doubled and ADAMTS13 levels decreased during and after transplantation up until day 30, when platelet count had normalized. Whereas prothrombin time and activated partial thromboplastin time were prolonged during transplantation, thrombin generation was within normal ranges, except during perioperative heparin administration. Fibrinogen, factor VIII levels, and clot lysis time were elevated up until day 30. In conclusion, children with end-stage liver disease are in tight hemostatic balance. During transplantation a temporary heparin-dependent hypocoagulable state is present, which rapidly converts to a hemostatic balance with distinct hypercoagulable features that persist until at least day 30. This hypercoagulable state may contribute to the risk of posttransplant thrombosis

Routine Postoperative Antithrombotic Therapy in Pediatric Liver Transplantation:Impact on Bleeding and Thrombotic Complications

BACKGROUND:  Hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT) are serious causes of morbidity and mortality after pediatric liver transplantation. To reduce thrombotic complications, routine antithrombotic therapy consisting of 1 week heparin followed by 3 months acetylsalicylic acid, was implemented in our pediatric liver transplant program in 2003. This study aimed to evaluate incidences of bleeding and thrombotic complications since the implementation of routine antithrombotic therapy and to identify risk factors for these complications. METHODS:  This retrospective cohort study includes 200 consecutive pediatric primary liver transplantations performed between 2003 and 2016. Uni- and multivariate logistic regression analysis, Kaplan-Meier method, and Cox regression analysis were used to evaluate recipient outcome. RESULTS:  HAT occurred in 15 (7.5%), PVT in 4 (2.0%), and venous outflow tract thrombosis in 2 (1.0%) recipients. Intraoperative vascular interventions (odds ratio [OR] 14.45 [95% confidence interval [CI] 3.75-55.67]), low recipient age (OR 0.81 [0.69-0.95]), and donor age (OR 0.96 [0.93-0.99]) were associated with posttransplant thrombosis. Clinically relevant bleeding occurred in 37%. Risk factors were high recipient age (OR 1.08 [1.02-1.15]), high Child-Pugh scores (OR 1.14 [1.02-1.28]), and intraoperative blood loss in mL/kg (OR 1.003 [1.001-1.006]). Both posttransplant thrombotic (hazard ratio [HR] 3.38 [1.36-8.45]; p = 0.009) and bleeding complications (HR 2.50 [1.19-5.24]; p = 0.015) significantly increased mortality. CONCLUSION:  In 200 consecutive pediatric liver transplant recipients receiving routine postoperative antithrombotic therapy, we report low incidences of posttransplant vascular complications. Posttransplant antithrombotic therapy seems to be a valuable strategy in pediatric liver transplantation. Identified risk factors for bleeding and thrombotic complications might facilitate a more personalized approach in antithrombotic therapy

How central obesity influences intra-abdominal pressure:a prospective, observational study in cardiothoracic surgical patients

Background: Intra-abdominal hypertension (IAH) is frequently present in critically ill patients and is an independent predictor for mortality. Better recognition of clinically important thresholds is necessary. Increased intra-abdominal pressure (IAP) is associated with renal dysfunction, and renal failure is one of the most consistently described organ dysfunctions associated with IAH. Obesity is also associated with kidney injury. The underlying mechanisms are not yet fully understood. Increased IAP may be a link in this association. The aim of this study was firstly to find the range in values of intra-abdominal pressure (IAP) in cardiothoracic surgery patients a secondly to investigate the relationship between central obesity, body mass index (BMI) and IAP and thirdly to investigate the relationship between IAP, inflammation and renal function in this population. Methods: Consecutive adult patients admitted to the cardiothoracic unit of the intensive care unit (ICU) after undergoing elective cardiothoracic surgery were included in this prospective, observational study. C-reactive protein (CRP) as a marker of inflammation and serum creatinine as a marker of renal function were measured pre- and postoperatively. Estimated glomerular filtration rates were calculated pre-and postoperatively. BMI was calculated. Waist circumference (WC), hip circumference (HC) and transvesical IAP were measured once directly after admission to the ICU postoperatively. Waist/ hip ratio (WHR) was calculated (WC divided by HC). Three definitions of central obesity were used. Central obesity was defined according to WC, WHR or median WHR. Results: In total, 186 patients undergoing cardiothoracic surgery were included. Mean IAP was 9.1 mmHg (SD 4.4). IAP = 12 mmHg was observed in 50 patients (26.9 %). IAP > 20 mmHg was measured in 4 patients (2.2 %). There was a positive correlation between IAP and BMI (r(2) = 0.05, p = 0.003). Correlations between IAP and WC (r(2) = 0.02, p = 0.054) and between IAP and WHR (r(2) = 0.01, p = 0.173) were not significant. There were no correlations between pre-or postoperative CRP and IAP (r(2) = 2.3 x 10(-4), p = 0.839 and r(2) = 0.013, p = 0.117, respectively). In obese patients postoperative CRP was significantly higher than in non-obese patients (p = 0.034). There were no correlations between pre-operative serum creatinine and IAP (r(2) = 3.3 x 10(-5), p = 0.938) or postoperative serum creatinine and IAP (r(2) = 0.003, p = 0.491). Conclusions: The range in IAP in patients undergoing cardiothoracic surgery was wide. There was a positive correlation between IAP and BMI. Correlations between IAP and indices for central obesity were not significant. In a multiple regression model BMI was a better predictor of IAP than WHR in this population. There were no correlations between pre- or postoperative CRP and IAP. Furthermore, this study did not find evidence for a relation between IAP and pre- and postoperative serum creatinine

Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin-based oxygen carrier perfusion solution

Ex situ dual hypothermic oxygenated machine perfusion (DHOPE) and normothermic machine perfusion (NMP) of donor livers may have a complementary effect when applied sequentially. While DHOPE resuscitates the mitochondria and increases hepatic adenosine triphosphate (ATP) content, NMP enables hepatobiliary viability assessment prior to transplantation. In contrast to DHOPE, NMP requires a perfusion solution with an oxygen carrier, for which red blood cells (RBC) have been used in most series. RBC, however, have limitations and cannot be used cold. We, therefore, established a protocol of sequential DHOPE, controlled oxygenated rewarming (COR), and NMP using a new hemoglobin-based oxygen carrier (HBOC)-based perfusion fluid (DHOPE-COR-NMP trial, NTR5972). Seven livers from donation after circulatory death (DCD) donors, which were initially declined for transplantation nationwide, underwent DHOPE-COR-NMP. Livers were considered transplantable if perfusate pH and lactate normalized, bile production was >= 10 mL and biliary pH > 7.45 within 150 minutes of NMP. Based on these criteria five livers were transplanted. The primary endpoint, 3-month graft survival, was a 100%. In conclusion, sequential DHOPE-COR-NMP using an HBOC-based perfusion fluid offers a novel method of liver machine perfusion for combined resuscitation and viability testing of suboptimal livers prior to transplantation

Patient-reported burden of intensified surveillance and surgery in high-risk individuals under pancreatic cancer surveillance

In high-risk individuals participating in a pancreatic cancer surveillance program, worrisome features warrant for intensified surveillance or, occasionally, surgery. Our objectives were to determine the patient-reported burden of intensified surveillance and/or surgery, and to assess post-operative quality of life and opinion of surgery. Participants in our pancreatic cancer surveillance program completed questionnaires including the Cancer Worry Scale (CWS) and the Hospital Anxiety and Depression Scale (HADS). For individuals who underwent intensified surveillance, questionnaires before, during, and ≥ 3 weeks after were analyzed. In addition, subjects who underwent intensified surveillance in the past 3 years or underwent surgery at any time, were invited for an interview, that included the Short-Form 12 (SF-12). A total of 31 high-risk individuals were studied. During the intensified surveillance period, median CWS scores were higher (14, IQR 7), as compared to before (12, IQR 9, P = 0.007) and after (11, IQR 7, P = 0.014), but eventually returned back to baseline (P = 0.823). Median HADS scores were low: 5 (IQR 6) for anxiety and 3 (IQR 5) for depression, and they were unaff

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity