Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation: A randomized, open-label, clinical trial.

BACKGROUND AND AIMS: In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial. APPROACH AND RESULTS: The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4). CONCLUSIONS: HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.

Maximizing the Donor Potential for Patients with Acute-on-Chronic Liver Failure Listed for Liver Transplant.

Owing to inherent limitations of static cold storage, marginal liver grafts from donors after circulatory death and extended criteria donors after brain death are prone to be discarded secondary to the increased risk of severe early allograft dysfunction and ischemic cholangiopathy. Marginal liver grafts resuscitated with hypothermic machine perfusion and normothermic machine perfusion demonstrate lower degree of ischemia-reperfusion injury and have decreased risk of severe early allograft dysfunction and ischemic cholangiopathy. Marginal grafts preserved by ex vivo machine perfusion technology can be used to rescue patients with acute-on-chronic liver failure who are underserved by the current deceased donor liver allocation system.

Clinical Application of Thromboelastography in Patients With Cirrhosis: A Single Center Experience.

INTRODUCTION: Thromboelastography (TEG) is a functional test of coagulation used to guide transfusions. Despite literature supporting its utility, its use remains limited to select populations. In patients with cirrhosis, conventional coagulation tests are notoriously inaccurate, and TEG may be a better measure of coagulopathy. We aimed to assess the utilization of TEG in patients with cirrhosis to steward blood transfusions in this high-risk group. METHODS: A single-center retrospective chart review of all patients ≥18 y old with a diagnosis of liver cirrhosis who had TEG results documented in the electronic medical record from January 1 to November 1, 2021. RESULTS: There were 277 TEG results on 89 patients with cirrhosis. Overall, 91% of the TEGs performed were associated with a clinical indication for transfusion. However, of the patients who were transfused, abnormal TEG values, including elevated R time and reduced maximum amplitude, did not correspond to transfusion of indicated blood products (fresh frozen plasma and platelets). A reduction in alpha angle showed a statistically significant association with transfusion of cryoprecipitate (P < 0.05). When assessing conventional coagulation tests, abnormal values were not significantly associated with transfusion (P = 0.07). CONCLUSIONS: Despite TEG suggesting that transfusions could be avoided in many cirrhotic patients, patients are still being transfused platelets and fresh frozen plasma in the absence of evidence of coagulopathy on TEG. Our finding suggests the need for education about appropriate utilization of TEG. More research is needed to understand the role of these tests to guide transfusion practices in patients with cirrhosis.

Pre-transplant Biomarkers of Immune Dysfunction Improve Risk Assessment of Post-transplant Mortality Compared to Conventional Clinical Risk Scores.

Introduction: There is a critical need to accurately stratify liver transplant (LT) candidates' risk of post-LT mortality prior to LT to optimize patient selection and avoid futility. Here, we compare previously described pre-LT clinical risk scores with the recently developed Liver Immune Frailty Index (LIFI) for prediction of post-LT mortality. LIFI measures immune dysregulation based on pre-LT plasma HCV IgG, MMP3 and Fractalkine. LIFI accurately predicts post-LT mortality, with LIFI-low corresponding to 1.4% 1-year post-LT mortality compared with 58.3% for LIFI-high (C-statistic=0.85). Methods: LIFI was compared to MELD, MELD-Na, MELD 3.0, D-MELD, MELD-GRAIL, MELD-GRAIL-Na, UCLA-FRS, BAR, SOFT, P-SOFT, and LDRI scores on 289 LT recipients based on waitlist data at the time of LT. Survival, hazard of early post-LT death, and discrimination power (C-statistic) were assessed. Results: LIFI showed superior discrimination (highest C-statistic) for post-LT mortality when compared to all other risk scores, irrespective of biologic MELD. On univariate analysis, the LIFI showed a significant correlation with mortality 6-months, as well as 1-, 3-, and 5-years. No other pre-LT scoring system significantly correlated with post-LT mortality. On bivariate adjusted analysis, African American race (p<0.05) and pre-LT cardiovascular disease (p=0.053) were associated with early- and long-term post-LT mortality. Patients who died within 1-yr following LT had a significantly higher incidence of infections, including 30-day and 90-day incidence of any infection, pneumonia, abdominal infections, and UTI (p<0.05). Conclusions: LIFI, which measures pre-LT biomarkers of immune dysfunction, more accurately predicts risk of post-LT futility compared with current clinical predictive models. Pre-LT assessment of immune dysregulation may be critical in predicting mortality after LT and may optimize selection of candidates with lowest risk of futile outcomes.

Using organ perfusion to optimize donor livers.

PURPOSE OF REVIEW: The shortage of donor organs has led to the use of marginal extended criteria donor (ECD) livers to increase access to liver transplant. Ex-vivo machine perfusion allows for treatment and assessment of organs during preservation, potentially facilitating safe use of ECD livers at risk for worse clinical outcomes. This article reviews the latest published literature on the application of ex-vivo machine perfusion technologies in liver transplantation. RECENT FINDINGS: Multiple randomized controlled trials on the use of hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) have been published in the past 5 years demonstrating improved graft function and decreased biliary complications after machine perfusion. Novel applications of machine perfusion include pretransplant organ viability testing, expansion to pediatric transplant, and prolonged preservation. SUMMARY: There is now a body of evidence that HMP and NMP treatment improves clinical outcomes in ECD livers. There is a wide horizon for future applications of these preservation techniques to further optimize donor livers and to facilitate more liver transplants for those on the waitlist.

Novel oxygenation technique for hypothermic machine perfusion of liver grafts: Validation in porcine Donation after Cardiac Death (DCD) liver model.

BACKGROUND: Hypothermic oxygenated machine perfusion improves outcomes in Liver Transplantation, but application is limited as O2 is supplied by a stationary circuit. A novel technique of O2 "pre-charge" in a portable pump would broaden use and further mitigate ischemia damage from organ transport. METHODS: Porcine DCD livers were randomized to static cold storage (SCS, n = 8) or hypothermic machine perfusion (HMP). HMP was stratified into HMP-O2 (n = 5), non-O2 open to air HMP-RA (n = 5), and non-O2 with sealed lids or no air HMP-NA (n = 5). HMP-O2 was "pre-charged" using 100% O2 delivered at 10 L/min over 15 min. Perfusate and tissue O2 tension (pO2), liver biopsies, and fluid chemistries were analyzed. RESULTS: "Pre-charge" achieves sustained tissue and perfusate pO2 vs others. HMP-O2 results in decreased markers of hepatocyte injury: ALT (p < 0.05) and LDH (p < 0.05), lower expression of CRP and higher expression of SOD1 vs SCS. This suggests decreased inflammation and improved ROS scavenging. CONCLUSIONS: "Pre-charge" is an effective technique, which allows portability and transport without an O2 source and improves graft parameters.

Liver Transplantation for Cholangiocarcinoma: Insights into the Prognosis and the Evolving Indications.

PURPOSE OF REVIEW: Cholangiocarcinoma (CCA) is a rare malignancy of the biliary ducts that can be classified as intrahepatic, perihilar, or distal based on anatomic location. Although surgical resection can be curative, complete excision with negative margins is often difficult to achieve. In patients with unresectable disease, long-term survival is rarely seen with medical therapy alone. A multimodal treatment approach, including liver transplantation (LT) for select patients with unresectable CCA, should be considered. RECENT FINDINGS: While currently only an approved indication for early, liver-limited, perihilar cholangiocarcinoma, promising results have been achieved for LT in localized intrahepatic disease. The absolute indication for transplant for intrahepatic tumors is currently the subject of multiple investigations. Continued advances in neoadjuvant/adjuvant therapy and better understanding of tumor biology may further augment the number of candidates for surgical therapies, with liver transplant acting as a promising tool to improve patient outcomes. Thorough consideration for any expansion in the indication for liver transplant in malignancy is necessary in order to balance patient outcomes with utilization of the scarce donor organ resources.