Outcomes of DCD liver transplantation using organs treated by hypothermic oxygenated perfusion before implantation

The ability to preserve metabolically active livers ex vivo for 1 week or more could allow repair of poor-quality livers that would otherwise be declined for transplantation. Current approaches for normothermic perfusion can preserve human livers for only 24 h. Here we report a liver perfusion machine that integrates multiple core physiological functions, including automated management of glucose levels and oxygenation, waste-product removal and hematocrit control. We developed the machine in a stepwise fashion using pig livers. Study of multiple ex vivo parameters and early phase reperfusion in vivo demonstrated the viability of pig livers perfused for 1 week without the need for additional blood products or perfusate exchange. We tested the approach on ten injured human livers that had been declined for transplantation by all European centers. After a 7-d perfusion, six of the human livers showed preserved function as indicated by bile production, synthesis of coagulation factors, maintained cellular energy (ATP) and intact liver structure.

/pdf/an-integrated-perfusion-machine-preserves-injured-human-4w3no0nfzo.pdf

An integrated perfusion machine preserves injured human livers for 1 week.

There is a limited access to liver transplantation, however, many organs are discarded based on subjective assessment only. Here we report the VITTAL clinical trial (ClinicalTrials.gov number NCT02740608) outcomes, using normothermic machine perfusion (NMP) to objectively assess livers discarded by all UK centres meeting specific high-risk criteria. Thirty-one livers were enroled and assessed by viability criteria based on the lactate clearance to levels ≤2.5 mmol/L within 4 h. The viability was achieved by 22 (71%) organs, that were transplanted after a median preservation time of 18 h, with 100% 90-day survival. During the median follow up of 542 days, 4 (18%) patients developed biliary strictures requiring re-transplantation. This trial demonstrates that viability testing with NMP is feasible and in this study enabled successful transplantation of 71% of discarded livers, with 100% 90-day patient and graft survival; it does not seem to prevent non-anastomotic biliary strictures in livers donated after circulatory death with prolonged warm ischaemia. The shortage of viable donated livers limits patient access to liver transplantation. Here the authors report the use of normothermic machine perfusion to help identify viable organs from livers discarded based on current clinical criteria, which are then transplanted to recipients in a single-arm clinical trial.

/pdf/transplantation-of-discarded-livers-following-viability-53cj4iynv3.pdf

Transplantation of discarded livers following viability testing with normothermic machine perfusion

Liver disease causing end organ failure is a growing cause of mortality. In most cases, the only therapy is liver transplantation. However, liver transplantation is a complex undertaking and its success is dependent on a number of factors. In particular, liver transplantation is subject to the risks of ischaemia-reperfusion injury (IRI). Liver IRI has significant effects on the function of a liver after transplantation. The cellular and molecular mechanisms governing IRI in liver transplantation are numerous. They involve multiple cells types such as liver sinusoidal endothelial cells, hepatocytes, Kupffer cells, neutrophils and platelets acting via an interconnected network of molecular pathways such as activation of toll-like receptor signalling, alterations in micro-RNA expression, production of ROS, regulation of autophagy and activation of hypoxia-inducible factors. Interestingly, the cellular and molecular events in liver IRI can be correlated with clinical risk factors for IRI in liver transplantation such as donor organ steatosis, ischaemic times, donor age, and donor and recipient coagulopathy. Thus, understanding the relationship of the clinical risk factors for liver IRI to the cellular and molecular mechanisms that govern it is critical to higher levels of success after liver transplantation. This in turn will help in the discovery of therapeutics for IRI in liver transplantation - a process that will lead to improved outcomes for patients suffering from end-stage liver disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/liv.14091

Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.15241

In situ normothermic perfusion of livers in controlled circulatory death donation may prevent ischemic cholangiopathy and improve graft survival

Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.

/pdf/a-randomized-trial-of-normothermic-preservation-in-liver-4cd6qwxjhm.pdf

A randomized trial of normothermic preservation in liver transplantation

A 24 year old woman presented with acute upper right abdominal pain radiating to the ipsilateral shoulder tip. She had undergone a laparoscopic cholecystectomy four days earlier without immediate complication. There was no other history of previous surgery.

Initial observations showed she was tachycardic with normal blood pressure and low grade pyrexia. On examination she was tender in the epigastrium and upper right quadrant, with no signs of peritonism. There were no other notable examination findings.

Her blood tests showed mildly raised liver transaminases and raised inflammatory markers, including a C reactive protein of greater than 200 mg/L. Urinalysis was unremarkable.

A magnetic resonance pancreatocholangiogram was obtained for further evaluation (fig 1⇓). This showed an area of abnormal T2 hyperintense (bright) signal above the right lobe of the liver that was tracking under the right hepatic margin.



Fig 1  T2 weighted coronal slice from magnetic resonance pancreatocholangiogram showing high signal around the liver, similar to the gastric contents (*)

https://www.bmj.com/content/bmj/357/bmj.j1481.full.pdf

Abdominal pain after surgery

A 38-year-old woman was admitted acutely from an inpatient psychiatric unit with a history of right loin to groin pain 1 day following vaginal instrumentation with a bottle. Her medical history included diabetes mellitus, cholecystectomy and borderline personality disorder with a history of self-harm.

She was feverish with generalised abdominal tenderness. The cervix and vagina were healthy with no discharge and no foreign body. Investigations revealed raised inflammatory markers, and normal transabdominal ultrasound scan, chest and pelvic X-rays. An abdominopelvic CT scan demonstrated two foreign bodies, in the right …

https://casereports.bmj.com/content/casereports/2016/bcr-2016-215222.full.pdf

Arvind Pallan

Papers

A randomized trial of normothermic preservation in liver transplantation

Abdominal pain after surgery

What on earth did I do with my pen