The Liver Retransplantation Risk Score: a prognostic model for survival after adult liver retransplantation.

High-risk combinations of recipient and graft characteristics are poorly defined for liver retransplantation (reLT) in the current era. We aimed to develop a risk model for survival after reLT using data from the European Liver Transplantation Registry, followed by internal and external validation. From 2006 to 2016, 85 067 liver transplants were recorded, including 5581 reLTs (6.6%). The final model included seven predictors of graft survival: recipient age, model for end-stage liver disease score, indication for reLT, recipient hospitalization, time between primary liver transplantation and reLT, donor age, and cold ischemia time. By assigning points to each variable in proportion to their hazard ratio, a simplified risk score was created ranging 0-10. Low-risk (0-3), medium-risk (4-5), and high-risk (6-10) groups were identified with significantly different 5-year survival rates ranging 56.9% (95% CI 52.8-60.7%), 46.3% (95% CI 41.1-51.4%), and 32.1% (95% CI 23.5-41.0%), respectively (P < 0.001). External validation showed that the expected survival rates were closely aligned with the observed mortality probabilities. The Retransplantation Risk Score identifies high-risk combinations of recipient- and graft-related factors prognostic for long-term graft survival after reLT. This tool may serve as a guidance for clinical decision-making on liver acceptance for reLT.

Utility of Preoperative Computed Tomography-Based Body Metrics in Relation to Postoperative Complications in Pediatric Liver Transplantation Recipients.

Computed tomography (CT)-derived body metrics such as skeletal muscle index (SMI), psoas muscle index (PMI), and subcutaneous fat area 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 their value in pediatric populations. This study assessed the relation between preoperative CT-based body metrics and postoperative short-term outcomes in pediatric LT recipients. 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 (<1, 1-10, and >10 years old). An optimal threshold for test performance was defined using Youden's J-statistic and receiver operating characteristic curve as appropriate. ScFI was significantly (P = 0.001) correlated with moderate to severe postoperative infections (CD grade 3-5) in children aged <1 year, 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 = -0.3; P = 0.01) and intensive care unit (ICU) stay (R = -0.3; P = 0.01) was observed in children aged <1 year. No other associations between CT-based body metrics and postoperative outcomes were shown. In children aged <1 year with cirrhotic liver disease undergoing LT, preoperative 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.

In Vitro Evaluation of Pro- and Anticoagulant Drugs in Children with End-Stage Liver Disease Undergoing Liver Transplantation.

BACKGROUND: Pro- and anticoagulant drugs are commonly used in pediatric liver transplantation to prevent and treat thrombotic and bleeding complications. However, the combination of baseline hemostatic changes in children with liver disease and additional changes induced by transplantation makes this very challenging. This study aimed to analyze the efficacy of clinically available pro- and anticoagulant drugs in plasma from children undergoing liver transplantation. METHODS: In vitro effects of pro- and anticoagulant drugs on thrombin generation capacity were tested in plasma samples of 20 children (≤ 16 years) with end-stage liver disease undergoing liver transplantation, and compared with 30 age-matched healthy controls. RESULTS: Addition of pooled normal plasma had no effect in patients or controls, while 4-factor prothrombin complex concentrate increased thrombin generation in both patients and controls, with enhanced activity in patients. At start of transplantation, dabigatran and unfractionated heparin had a higher anticoagulant potency in patients, whereas 30 days after transplantation low molecular weight heparin was slightly less effective in patients. Effects of rivaroxaban were comparable between patients and controls. CONCLUSION: This study revealed important differences in efficacy of commonly used pro- and anticoagulant drugs in children with end-stage liver disease undergoing liver transplantation. Therefore, dose adjustments of these drugs may be required. The results of this study may be helpful in the development of urgently needed protocols for strategies to prevent and treat bleeding and thrombotic complications in pediatric liver transplantation.

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.

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.

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.

Transplantation of High-risk Donor Livers After Ex Situ Resuscitation and Assessment Using Combined Hypo- and Normothermic Machine Perfusion: A Prospective Clinical Trial.

OBJECTIVE: The aim of this study was to evaluate sequential hypothermic and normothermic machine perfusion (NMP) as a tool to resuscitate and assess viability of initially declined donor livers to enable safe transplantation. SUMMARY BACKGROUND DATA: Machine perfusion is increasingly used to resuscitate and test the function of donor livers. Although (dual) hypothermic oxygenated machine perfusion ([D]HOPE) resuscitates livers after cold storage, NMP enables assessment of hepatobiliary function. METHODS: In a prospective clinical trial, nationwide declined livers were subjected to ex situ NMP (viability assessment phase), preceded by 1-hour DHOPE (resuscitation phase) and 1 hour of controlled oxygenated rewarming (COR), using a perfusion fluid containing an hemoglobin-based oxygen carrier. During the first 2.5 hours of NMP, hepatobiliary viability was assessed, using predefined criteria: perfusate lactate <1.7 mmol/L, pH 7.35 to 7.45, bile production >10 mL, and bile pH >7.45. Livers meeting all criteria were accepted for transplantation. Primary endpoint was 3-month graft survival. RESULTS: Sixteen livers underwent DHOPE-COR-NMP. All livers were from donors after circulatory death, with median age of 63 (range 42-82) years and median Eurotransplant donor risk index of 2.82. During NMP, all livers cleared lactate and produced sufficient bile volume, but in 5 livers bile pH remained <7.45. The 11 (69%) livers that met all viability criteria were successfully transplanted, with 100% patient and graft survival at 3 and 6 months. Introduction of DHOPE-COR-NMP increased the number of deceased donor liver transplants by 20%. CONCLUSIONS: Sequential DHOPE-COR-NMP enabled resuscitation and safe selection of initially declined high-risk donor livers, thereby increasing the number of transplantable livers by 20%. TRIAL REGISTRATION: www.trialregister.nl; NTR5972.

Transplantation of high-risk donor livers after resuscitation and viability assessment using a combined protocol of oxygenated hypothermic, rewarming and normothermic machine perfusion: study protocol for a prospective, single-arm study (DHOPE-COR-NMP trial).

INTRODUCTION: Extended criteria donor (ECD) livers are increasingly accepted for transplantation in an attempt to reduce the gap between the number of patients on the waiting list and the available number of donor livers. ECD livers; however, carry an increased risk of developing primary non-function (PNF), early allograft dysfunction (EAD) or post-transplant cholangiopathy. Ischaemia-reperfusion injury (IRI) plays an important role in the development of these complications. Machine perfusion reduces IRI and allows for reconditioning and subsequent evaluation of liver grafts. Single or dual hypothermic oxygenated machine perfusion (DHOPE) (4°C-12°C) decreases IRI by resuscitation of mitochondria. Controlled oxygenated rewarming (COR) may further reduce IRI by preventing sudden temperature shifts. Subsequent normothermic machine perfusion (NMP) (37°C) allows for ex situ viability assessment to facilitate the selection of ECD livers with a low risk of PNF, EAD or post-transplant cholangiopathy. METHODS AND ANALYSIS: This prospective, single-arm study is designed to resuscitate and evaluate initially nationwide declined ECD livers. End-ischaemic DHOPE will be performed for the initial mitochondrial and graft resuscitation, followed by COR of the donor liver to a normothermic temperature. Subsequently, NMP will be continued to assess viability of the liver. Transplantation into eligible recipients will proceed if all predetermined viability criteria are met within the first 150 min of NMP. To facilitate machine perfusion at different temperatures, a perfusion solution containing a haemoglobin-based oxygen carrier will be used. With this protocol, we aim to transplant extra livers. The primary endpoint is graft survival at 3 months after transplantation. ETHICS AND DISSEMINATION: This protocol was approved by the medical ethical committee of Groningen, METc2016.281 in August 2016 and registered in the Dutch Trial registration number TRIAL REGISTRATION NUMBER: NTR5972, NCT02584283.

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.

First report of successful transplantation of a pediatric donor liver graft after hypothermic machine perfusion.

One of the main limiting factors in pediatric liver transplantation is donor availability. For adults, DCD liver grafts are increasingly used to expand the donor pool. To improve outcome after DCD liver transplantation, ex situ machine perfusion is used as an alternative organ preservation strategy, with the supplemental value of providing oxygen to the graft during preservation. We here report the first successful transplantation of a pediatric DCD liver graft after hypothermic oxygenated machine perfusion. The full-size liver graft was derived from a 13-year-old, female DCD donor and was end-ischemic pretreated with dual hypothermic oxygenated machine perfusion. Arterial and portal pressures were set at 18 and 4 mm Hg, slightly lower than protocolized settings for adult livers. During 2 hours of machine perfusion, portal and arterial flows increased from 100 to 210 mL/min and 30 to 63 mL/min, respectively. The pretreated liver graft was implanted in a 16-year-old girl with progressive familial intrahepatic cholestasis type 2. Postoperative AST, ALT, and prothrombin time normalized within a week. The recipient quickly recovered and was discharged from the hospital after 18 days. One year after transplantation, she is in excellent condition with a completely normal liver function and histology. This case is the first report of successful transplantation of a pediatric DCD liver graft after hypothermic oxygenated machine perfusion and illustrates the potential role of ex situ machine perfusion in expanding the donor pool and improving outcome after pediatric liver transplantation.

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.

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 × 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 × 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.