Ignite Creation Date:
2024-05-06 @ 1:09 PM
Last Modification Date:
2024-10-26 @ 1:09 PM
Study NCT ID:
NCT03946852
Status:
NOT_YET_RECRUITING
Last Update Posted:
2019-05-13
First Post:
2019-05-09
Brief Title:
Abdominal Regional Perfusion in Donation After Cardiac Death for Multi-Organ Transplantation
Sponsor:
London Health Sciences Centre
Organization:
London Health Sciences Centre
Study Overview
Official Title:
Abdominal Regional Perfusion in Donation After Cardiac Death for Multi-Organ Transplantation
Status:
NOT_YET_RECRUITING
Status Verified Date:
2019-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The main purpose of this study is to increase the pool of organs available for donation by performing ARP to recondition donation after cardiac death DCD organs prior to transplantation We will compare the outcomes of our ARP DCD liver transplants with historical data to determine the efficacy of this treatment compared to transplantation with standard DCD and donation after brain death DBD organs We will also analyze biological samples from donors and recipients and compare them with outcome data in an effort to determine if any biological markers are able to predict the qualitysuccess of the grafts
Detailed Description:
Liver Transplantation and Limitations of DCD Transplantation
Liver transplantation LT is the sole curative therapy for end stage liver disease and has emerged as the treatment of choice for hepatocellular carcinoma Recent evidence has also demonstrated efficacy in a growing number of malignancies including intraextra-hepatic cholangiocarcinoma metastatic neuro-endocrine tumors and colorectal liver metastases Despite these advantages LT is limited by the availability of suitable donor organs resulting in lengthened LT waitlist times However during this waiting period patients may deteriorate making them ineligible for LT In the US 16000 patients are listed for LT and approximately 2000 die annually while waiting for suitable organs In 2017 over 500 Canadians were on a waiting list for LT and nearly 200 died or withdrew from the transplant list while waiting Additionally while LT secondary to hepatitis C is declining nonalcoholic steatohepatitis alcoholic liver disease and transplant oncology indications are growing increasing the overall demand for liver transplant
One strategy to expand the donor pool has been to optimize utilization of organs from donation after cardiac death DCD While outcomes of DCD kidney pancreas and lung transplants show similar patient and graft survival to donation after brain death DBD transplants DCD livers have worse patient and graft survival higher complications and costs along with worse quality of life DCD liver grafts have twice the rate of early complications including primary non-function PNF and early allograft dysfunction EAD EAD is a transient condition with the potential for graft function recovery whereas PNF is a more severe complication leading to graft failure requiring emergency re-transplantation In the long term the use of DCD liver allografts is associated with a 10 fold increase in biliary complications typically resulting in graft loss or death Moreover there is a high cost associated with complications and readmissions following LT which can be upwards of 50000 per patient Studies investigating factors contributing to these costs have revealed that DCD allografts had the greatest impact on transplant costs Consequently initial enthusiasm for the use of DCD livers for LT has waned such that utilization is restricted to only ideal DCD livers from younger donors with short warm and cold ischemia times Developing methodologies to reduce the complications associated with DCD organs and improve overall outcomes would have an immense impact on the lives of transplant patients while concurrently reducing costs on the healthcare system
Abdominal Regional Perfusion and Limitations of Normothermic Machine Perfusion
Conventional DCD recovery utilizes a rapid recovery technique which flushes abdominal organs with cold preservation solution to slow cellular metabolism and evacuate bloodclots to preserve the integrity of the microvasculature This is preceded by the agonal phase between withdrawal of life support and cessation of cardiac function During this period abdominal organs are subject to warm ischemia resulting in accumulation of toxic metabolites depletion of intracellular energy and anti-oxidant stores leading to exacerbation of ischemia reperfusion at the time of implantation
Abdominal Regional Perfusion ARP is a technique that has been developed to recondition DCD organs prior to transplantation through the perfusion of abdominal organs in-situ with re-oxygenated blood This process reverses the effects of ischemia and hypoxia by restoring cellular energy stores and reducing oxygen free-radicals Additionally this period of restored abdominal perfusion also allows for functional evaluation of organ viability prior to graft use through measurement of donor serumbile biochemistry throughout the perfusion process thereby maximizing the yield of high quality grafts and avoiding the use of grafts that have impaired function
In the few studies published to date ARP has demonstrated a decrease in biliary complications by 86 a decrease in ischemic cholangiopathy rates from 27 to 0 and a drop in EAD from 32 to 12 Most importantly graft loss at 30 days was only 2 in ARP compared with 12 in conventional DCD LT Emerging evidence suggests that with ARP transplants performed using DCD organs can result in outcomes similar to conventional DBD donors In addition other investigators have successfully used ARP to further expand the DCD donor pool by including donors beyond the traditional age limit of 50 years to patients greater than 75 This approach has the potential to dramatically increase the donor pool and has even been demonstrated to improve the quality of other organs used for transplant including kidney and heart transplantation
Although normothermic machine perfusion NMP systems have demonstrated non-inferiority compared to static cold storage in LT by dropping perfusate lactate improving intraoperative mean arterial pressure reducing vasopressor requirements and reducing blood product transfusions the majority 80 of these donor livers were procured from DBD donors in which static cold storage continues to be the standard of care based upon three decades of favorable outcomes There remains a paucity of data demonstrating the benefit of NMP in the setting of expanded criteria livers from donors with advanced age steatosis and DCD livers where ARP has been of proven benefit In addition ARP may also be advantageous due to its in-situ nature with preservation of the neurohormonal axis and communication with other abdominal organs Few clinical studies have investigated the role of measurable variables in predicting ARP-DCD transplant outcomes however some correlation has been found between the effects of lactate levels transaminase levels and the level of fibrosis on donor organ function To address these unknowns an additional goal of this study will be to identify possible mediators for the improved outcomes with abdominal-regional perfusion and evaluate the utility of biomarkers to predict graft function
Liver transplantation LT is the sole curative therapy for end stage liver disease and has emerged as the treatment of choice for hepatocellular carcinoma Recent evidence has also demonstrated efficacy in a growing number of malignancies including intraextra-hepatic cholangiocarcinoma metastatic neuro-endocrine tumors and colorectal liver metastases Despite these advantages LT is limited by the availability of suitable donor organs resulting in lengthened LT waitlist times However during this waiting period patients may deteriorate making them ineligible for LT In the US 16000 patients are listed for LT and approximately 2000 die annually while waiting for suitable organs In 2017 over 500 Canadians were on a waiting list for LT and nearly 200 died or withdrew from the transplant list while waiting Additionally while LT secondary to hepatitis C is declining nonalcoholic steatohepatitis alcoholic liver disease and transplant oncology indications are growing increasing the overall demand for liver transplant
One strategy to expand the donor pool has been to optimize utilization of organs from donation after cardiac death DCD While outcomes of DCD kidney pancreas and lung transplants show similar patient and graft survival to donation after brain death DBD transplants DCD livers have worse patient and graft survival higher complications and costs along with worse quality of life DCD liver grafts have twice the rate of early complications including primary non-function PNF and early allograft dysfunction EAD EAD is a transient condition with the potential for graft function recovery whereas PNF is a more severe complication leading to graft failure requiring emergency re-transplantation In the long term the use of DCD liver allografts is associated with a 10 fold increase in biliary complications typically resulting in graft loss or death Moreover there is a high cost associated with complications and readmissions following LT which can be upwards of 50000 per patient Studies investigating factors contributing to these costs have revealed that DCD allografts had the greatest impact on transplant costs Consequently initial enthusiasm for the use of DCD livers for LT has waned such that utilization is restricted to only ideal DCD livers from younger donors with short warm and cold ischemia times Developing methodologies to reduce the complications associated with DCD organs and improve overall outcomes would have an immense impact on the lives of transplant patients while concurrently reducing costs on the healthcare system
Abdominal Regional Perfusion and Limitations of Normothermic Machine Perfusion
Conventional DCD recovery utilizes a rapid recovery technique which flushes abdominal organs with cold preservation solution to slow cellular metabolism and evacuate bloodclots to preserve the integrity of the microvasculature This is preceded by the agonal phase between withdrawal of life support and cessation of cardiac function During this period abdominal organs are subject to warm ischemia resulting in accumulation of toxic metabolites depletion of intracellular energy and anti-oxidant stores leading to exacerbation of ischemia reperfusion at the time of implantation
Abdominal Regional Perfusion ARP is a technique that has been developed to recondition DCD organs prior to transplantation through the perfusion of abdominal organs in-situ with re-oxygenated blood This process reverses the effects of ischemia and hypoxia by restoring cellular energy stores and reducing oxygen free-radicals Additionally this period of restored abdominal perfusion also allows for functional evaluation of organ viability prior to graft use through measurement of donor serumbile biochemistry throughout the perfusion process thereby maximizing the yield of high quality grafts and avoiding the use of grafts that have impaired function
In the few studies published to date ARP has demonstrated a decrease in biliary complications by 86 a decrease in ischemic cholangiopathy rates from 27 to 0 and a drop in EAD from 32 to 12 Most importantly graft loss at 30 days was only 2 in ARP compared with 12 in conventional DCD LT Emerging evidence suggests that with ARP transplants performed using DCD organs can result in outcomes similar to conventional DBD donors In addition other investigators have successfully used ARP to further expand the DCD donor pool by including donors beyond the traditional age limit of 50 years to patients greater than 75 This approach has the potential to dramatically increase the donor pool and has even been demonstrated to improve the quality of other organs used for transplant including kidney and heart transplantation
Although normothermic machine perfusion NMP systems have demonstrated non-inferiority compared to static cold storage in LT by dropping perfusate lactate improving intraoperative mean arterial pressure reducing vasopressor requirements and reducing blood product transfusions the majority 80 of these donor livers were procured from DBD donors in which static cold storage continues to be the standard of care based upon three decades of favorable outcomes There remains a paucity of data demonstrating the benefit of NMP in the setting of expanded criteria livers from donors with advanced age steatosis and DCD livers where ARP has been of proven benefit In addition ARP may also be advantageous due to its in-situ nature with preservation of the neurohormonal axis and communication with other abdominal organs Few clinical studies have investigated the role of measurable variables in predicting ARP-DCD transplant outcomes however some correlation has been found between the effects of lactate levels transaminase levels and the level of fibrosis on donor organ function To address these unknowns an additional goal of this study will be to identify possible mediators for the improved outcomes with abdominal-regional perfusion and evaluate the utility of biomarkers to predict graft function
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None