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IntroductionPatients with cirrhosis undergoing liver transplantation frequently exhibit systemic inflammation, coagulation derangements, and edema, indicating endothelial dysfunction. This syndrome may worsen after ischemia-reperfusion injury of the liver graft, coincident with organ dysfunction that worsens patient outcomes. Little is known about changes in endothelial permeability during liver transplantation. We hypothesized that sera from these patients would increase permeability in cultured human endothelial cells ex vivo.MethodsAdults with cirrhosis presenting for liver transplantation provided consent for blood collection during surgery. Sera were prepared at five time points spanning the entire operation. The barrier function of human pulmonary microvascular endothelial cells in culture was assessed by transendothelial resistance measured using the ECIS ZΘ system. Confluent cells from two different endothelial cell donors were stimulated with human serum from liver transplant patients. Pooled serum from healthy men and purified inflammatory agonists served as controls. The permeability response to serum was quantified as the area under the normalized resistance curve. Responses were compared between time points and analyzed for associations with clinical characteristics of liver transplant patients and their grafts.ResultsLiver transplant sera from all time points during surgery-induced permeability in both endothelial cell lines. The magnitude of permeability change was heterogeneous between patients, and there were differences in the effects of sera on the two endothelial cell lines. In one of the cell lines, the severity of liver disease was associated with greater permeability at the start of surgery. In the same cell line, serum collected 15 min after liver reperfusion induced significantly more permeability as compared to that collected at the start of surgery. Early postreperfusion sera from patients undergoing living donor transplants induced more permeability than sera from deceased donor transplants. Sera from two exemplary cases of patients on preoperative dialysis, and one patient with an unexpectedly long warm ischemia time of the liver graft, induced exaggerated and prolonged endothelial permeability.DiscussionSerum from patients with cirrhosis undergoing liver transplantation induces permeability of cultured human pulmonary microvascular endothelial cells. Increased endothelial permeability during liver transplantation may contribute to organ injury and present a target for future therapeutics.

IntroductionCatecholamine vasopressors such as norepinephrine are the standard drugs used to maintain mean arterial pressure during liver transplantation. At high doses, catecholamines may impair organ perfusion. Angiotensin II is a peptide vasoconstrictor that may improve renal perfusion pressure and glomerular filtration rate, a haemodynamic profile that could reduce acute kidney injury. Angiotensin II is approved for vasodilatory shock but has not been rigorously evaluated for treatment of hypotension during liver transplantation. The objective is to assess the efficacy of angiotensin II as a second-line vasopressor infusion during liver transplantation. This trial will establish the efficacy of angiotensin II in decreasing the dose of norepinephrine to maintain adequate blood pressure. Completion of this study will allow design of a follow-up, multicentre trial powered to detect a reduction of organ injury in liver transplantation.Methods and analysisThis is a double-blind, randomised clinical trial. Eligible subjects are adults with a Model for End-Stage Liver Disease Sodium Score ≥25 undergoing deceased donor liver transplantation. Subjects are randomised 1:1 to receive angiotensin II or saline placebo as the second-line vasopressor infusion. The study drug infusion is initiated on reaching a norepinephrine dose of 0.05 µg kg-1 min-1 and titrated per protocol. The primary outcome is the dose of norepinephrine required to maintain a mean arterial pressure ≥65 mm Hg. Secondary outcomes include vasopressin or epinephrine requirement and duration of hypotension. Safety outcomes include incidence of thromboembolism within 48 hours of the end of surgery and severe hypertension. An intention-to-treat analysis will be performed for all randomised subjects receiving the study drug. The total dose of norepinephrine will be compared between the two arms by a one-tailed Mann-Whitney U test.Ethics and disseminationThe trial protocol was approved by the local Institutional Review Board (#20-30948). Results will be posted on ClinicalTrials.gov and published in a peer-reviewed journal.Trial registration numberClinicalTrials.govNCT04901169.

BACKGROUND: The impact of albumin use during major surgery is unknown, and a dearth of evidence governing its use in major noncardiac surgery has long precluded its standardization in clinical guidelines. OBJECTIVE: In this study, we investigate institutional variation in albumin use among medical centers in the United States during major noncardiac surgery and explore the association of intraoperative albumin administration with important postoperative outcomes. METHODS: The study is an observational retrospective cohort analysis performed among 54 U.S. hospitals in the Multicenter Perioperative Outcomes Group and includes adult patients who underwent major noncardiac surgery under general anesthesia between January 2014 and June 2020. The primary endpoint was the incidence of albumin administration. Secondary endpoints are acute kidney injury (AKI), net-positive fluid balance, pulmonary complications, and 30-day mortality. Albumin-exposed and albumin-unexposed cases were compared within a propensity score-matched cohort to evaluate associations of albumin use with outcomes. RESULTS: Among 614,215 major surgeries, predominantly iso-oncotic albumin was administered in 15.3% of cases and featured significant inter-institutional variability in use patterns. Cases receiving intraoperative albumin involved patients of higher American Society of Anesthesiologists physical status and featured larger infused crystalloid volumes, greater blood loss, and vasopressor use. Overall, albumin was most often administered at high-volume surgery centers with academic affiliation, and within a propensity score-matched cohort (n=153,218), the use of albumin was associated with AKI (aOR 1.24, 95% CI 1.20-1.28, P

The wait times for patients with hepatocellular carcinoma (HCC) listed for liver transplant are longer than ever, which has led to an increased reliance on the use of pre-operative LRTs. The impact that multiple rounds of LRTs have on peri-operative outcomes following transplant is unknown. This was a retrospective single center analysis of 298 consecutive patients with HCC who underwent liver transplant (January 2017 to May 2021). The data was obtained from two institution-specific databases and the TransQIP database. Of the 298 patients, 27 (9.1%) underwent no LRTs, 156 (52.4%) underwent 1-2 LRTs, and 115 (38.6%) underwent ≥3 LRTs prior to LT. The patients with ≥3 LRTs had a significantly higher rate of bile leak compared to patients who received 1-2 LRTs (7.0 vs. 1.3%, p = 0.014). Unadjusted and adjusted regression analyses demonstrated a significant association between the total number of LRTs administered and bile leak, but not rates of overall biliary complications. The total number of LRTs was not significantly associated with any other peri-operative or post-operative outcome measure. These findings support the aggressive use of LRTs to control HCC in patients awaiting liver transplant, with further evaluation needed to confirm the biliary leak findings.

BackgroundMost patients are listed for liver transplant (LT) following extensive workup as outpatients ("conventional evaluation"). Some patients undergo urgent evaluation as inpatients after being transferred to a transplant center ("expedited evaluation"). We hypothesized that expedited patients would have inferior survival due to disease severity at the time of transplant and shorter workup time.MethodsPatients who underwent evaluation for LT at our institution between 2012 and 2016 were retrospectively reviewed. The expedited and conventional cohorts were defined as above. Living donor LT recipients, combined liver-kidney recipients, acute liver failure patients, and re-transplant patients were excluded. We compared patient characteristics and overall survival between patients who received a transplant following expedited evaluation and those who did not, and between LT recipients based on expedited or conventional evaluation.ResultsFive-hundred and nine patients were included (110 expedited, 399 conventional). There was no difference in graft or patient survival at 1 year for expedited versus conventional LT recipients. In multivariable analysis of overall survival, only Donor Risk Index (HR 1.97, CI 1.04-3.73, P = .037, per unit increase) was associated with increased risk of death.ConclusionsPatients who underwent expedited evaluation for LT had significant demographic and clinical differences from patients who underwent conventional evaluation, but comparable post-transplant survival.

Early prediction of whether a liver allograft will be utilized for transplantation may allow better resource deployment during donor management and improve organ allocation. The national donor management goals (DMG) registry contains critical care data collected during donor management. We developed a machine learning model to predict transplantation of a liver graft based on data from the DMG registry.MethodsSeveral machine learning classifiers were trained to predict transplantation of a liver graft. We utilized 127 variables available in the DMG dataset. We included data from potential deceased organ donors between April 2012 and January 2019. The outcome was defined as liver recovery for transplantation in the operating room. The prediction was made based on data available 12-18 h after the time of authorization for transplantation. The data were randomly separated into training (60%), validation (20%), and test sets (20%). We compared the performance of our models to the Liver Discard Risk Index.ResultsOf 13 629 donors in the dataset, 9255 (68%) livers were recovered and transplanted, 1519 recovered but used for research or discarded, 2855 were not recovered. The optimized gradient boosting machine classifier achieved an area under the curve of the receiver operator characteristic of 0.84 on the test set, outperforming all other classifiers.ConclusionsThis model predicts successful liver recovery for transplantation in the operating room, using data available early during donor management. It performs favorably when compared to existing models. It may provide real-time decision support during organ donor management and transplant logistics.

Background: Scoring systems have been proposed to select donation after circulatory death (DCD) donors and recipients for liver transplantation (LT). We hypothesized that complex scoring systems derived in large datasets might not predict outcomes locally. Methods: Based on 1-year DCD-LT graft survival predictors in multivariate logistic regression models, we designed, validated, and compared a simple index using the University of California, San Francisco (UCSF) cohort (n = 136) and a universal-comprehensive (UC)-DCD score using the United Network for Organ Sharing (UNOS) cohort (n = 5,792) to previously published DCD scoring systems. Results: The total warm ischemia time (WIT)-index included donor WIT (dWIT) and hepatectomy time (dHep). The UC-DCD score included dWIT, dHep, recipient on mechanical ventilation, transjugular-intrahepatic-portosystemic-shunt, cause of liver disease, model for end-stage liver disease, body mass index, donor/recipient age, and cold ischemia time. In the UNOS cohort, the UC-score outperformed all previously published scores in predicting DCD-LT graft survival (AUC: 0.635 vs. ≤0.562). In the UCSF cohort, the total WIT index successfully stratified survival and biliary complications, whereas other scores did not. Conclusion: DCD risk scores generated in large cohorts provide general guidance for safe recipient/donor selection, but they must be tailored based on non-/partially-modifiable local circumstances to expand DCD utilization.

BackgroundThe novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease has transformed innumerable aspects of medical practice, particularly in the field of transplantation.Main bodyHere we describe a single-center approach to creating a generalizable, comprehensive, and graduated set of recommendations to respond in stepwise fashion to the challenges posed by these conditions, and the underlying principles guiding such decisions.ConclusionsCreation of a stepwise plan will allow transplant centers to respond in a dynamic fashion to the ongoing challenges posed by the COVID-19 pandemic.

Rates of kidney transplantation vary substantially across dialysis facilities in the United States. Whether distance between the dialysis facility and transplant center associates with variations in transplantation rates has not been examined.MethodsWe performed a retrospective study of adults treated with dialysis between 2005 and 2015, according to the US Renal Data System. We examined the association between distance from dialysis facility to transplant center and time to kidney transplantation (primary outcome) and waitlist registration (secondary outcome) using Fine-Gray models. We also performed sensitivity analyses using the distance from each patient's dialysis facility to the nearest transplant center as the predictor so that patients who were never registered on the waitlist (and therefore would not have a transplant center) could be included.ResultsIn total, 178 885 waitlisted patients were included for our primary analysis. As distance between dialysis facility and transplant center increased, lower hazard of transplantation (subhazard ratio [HR], 0.92; 95% confidence interval [CI], 0.91-0.94, if distance was 10 to

BACKGROUND:During kidney transplantation, intraoperative fluid management can affect post-transplant graft function. It is unclear whether or not central venous pressure (CVP) monitoring is required to guide fluid therapy during kidney transplantation. METHODS:We compared post-transplant graft function in recipients of living donor kidney transplants between August 2006 and March 2009 based on the use or absence of intraoperative CVP monitoring. Graft function, assessed using the creatinine reduction ratio on postoperative day 2 (CCR2), was evaluated by multivariable linear regression analysis and in a propensity-matched cohort. RESULTS:Two hundred and ninety patients were included in the analysis. Central venous pressure was monitored in 84 patients (29%). There was no difference in post-transplant graft function, as measured by CCR2, between patients with and without CVP monitoring in both unadjusted and multivariable-adjusted analyses. There were also no statistically significant differences in CCR2, delayed graft function, or 3-month renal function between those monitored with CVP and those without, in the propensity-matched cohort. CONCLUSIONS:In this single-center analysis, immediate post-transplant renal function was not associated with the use of intraoperative CVP monitoring.

Background: The post‐operative course after Liver Transplantation (LT) can be complicated by early allograft dysfunction (EAD), primary nonfunction (PNF) and death. A lactate concentration at the end of transplant of ≥5 mmol/L was recently proposed as a predictive marker of PNF, EAD, and mortality; this study aimed to validate these previous reports in a large single center cohort. Methods: This retrospective cohort study included adult liver transplant recipients who received grafts from deceased donors at our center between June 2012 and May 2021. Receiver operating characteristic (ROC) curves for the lactate concentration at the end of transplantation were computed to determine the AUC for PNF, EAD and mortality at 90 days. Results: In our cohort of 1137 cases, the AUCs for lactate to predict EAD, PNF and mortality were respectively.56 (95% confidence interval [CI]:.53–.60),.69 (95% CI:.52–.85), and.74 (95% CI:.63–.84). Conclusion: The clinical value of lactate concentration at the end of transplantation to predict PNF, EAD and mortality at 90 days was, at best, modest, as shown by the relatively low AUCs. Our findings cannot validate previous reports that the lactate level alone is a good predictor of poor outcomes after liver transplantation. [ABSTRACT FROM AUTHOR]

Background: Outcome data for the great majority of liver normothermic machine perfusion (NMP) cases derive from the strict confines of clinical trials. Detailed specifics regarding the intraoperative and early postoperative impact of NMP on reperfusion injury and its sequelae during real‐world use of this emerging technology remain largely unavailable. Methods: We analyzed transplants performed in a 3‐month pilot period during which surgeons invoked commercial NMP at their discretion. Living donor, multi‐organ, and hypothermic machine perfusion transplants were excluded. Results: Intraoperatively, NMP (n = 24) compared to static cold storage (n = 25) recipients required less peri‐reperfusion bolus epinephrine (0 vs. 60 μg; p <.001) and post‐reperfusion fresh frozen plasma (2.5 vs. 7.0 units; p =.0069), platelets (.0 vs. 2.0 units; p =.042), and hemostatic agents (0% vs. 24%; p =.010). Time from incision to venous reperfusion did not differ (3.6 vs. 3.1; p =.095) but time from venous reperfusion to surgery end was shorter for NMP recipients (2.3 vs. 2.8 h; p =.0045). Postoperatively, NMP recipients required fewer red blood cell (1.0 vs. 4.0 units; p =.0083) and fresh frozen plasma (4.0 vs. 7.0 units; p =.046) transfusions, had shorter intensive care unit stays (33.5 vs. 58.4 h; p =.012), and experienced less early allograft dysfunction according to both the Model for Early Allograft Function Score (3.4 vs. 5.0; p =.0047) and peak AST within 10 days of transplant (619 vs. 1,181 U/L; p =.036). Liver acceptance for the corresponding recipient was conditional on NMP use for 63% (15/24) of cases. Conclusion: Real‐world NMP use was associated with significantly lower intensity of reperfusion injury and intraoperative and postoperative care that may translate into patient benefit. [ABSTRACT FROM AUTHOR]

Background: Delayed graft function (DGF) after kidney transplantation is a common occurrence and correlates with poor graft and patient outcomes. Donor characteristics and care are known to impact DGF. We attempted to show the relationship between achievement of specific donor management goals (DMG) and DGF. Methods: This is a retrospective case‐control study using data from 14 046 adult kidney donations after brain death from hospitals in 18 organ procurement organizations (OPOs) which were transplanted to adult recipients between 2012 and 2018. Data on DMG compliance and donor, recipient, and ischemia‐related factors were used to create multivariable logistic regression models. Results: The overall rate of DGF was 29.4%. Meeting DMGs for urine output and vasopressor use were associated with decreased risk of DGF. Sensitivity analyses performed with different imputation methods, omitting recipient factors, and analyzing multiple time points yielded largely consistent results. Conclusions: The development of DMGs continues to show promise in improving outcomes in the kidney transplant recipient population. Studies have already shown increased kidney utilization in smaller cohorts, as well as other organs, and shown decreased rates of DGF. Additional research and analysis are required to assess interactions between meeting DMGs and correlation versus causality in DMGs and DGF. [ABSTRACT FROM AUTHOR]