Preservation of Porcine Non–heart-Beating Donor Livers by Sequential Cold Storage and Warm Perfusion

Reddy, Srikanth; Bhattacharjya, Shantanu; Maniakin, N; Greenwood, Joanne; Guerreiro, Dino; Hughes, David; Imber, Charles; Pigott, David; Fuggle, Susan V.; Taylor, Richard; Friend, Peter J.

doi:10.1097/01.tp.0000119206.63326.56

Cited by 120 publications

(125 citation statements)

References 25 publications

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“…In both situations the whole cascade of I/R injury will be activated without a conditioning or protective effect of MP. [33][34][35] Another limitation of our study is the ex situ reperfusion model. Although this model, which has also been used by other groups, 9,12,14,15 allowed us to assess viability and injury of hepatocytes and cholangiocytes, we did not confirm our findings in a transplantation model.…”

Section: Discussionmentioning

confidence: 99%

End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

Westerkamp

Mahboub²,

Meyer

et al. 2015

Liver Transpl

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A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation. Liver Transpl 21:1300-1311, 2015. V C 2015 AASLD.Received March 17, 2015; accepted June 8, 2015.Ischemic cholangiopathy, also known as nonanastomotic biliary strictures (NAS), is one of the most prevalent and troublesome complications after liver transplantation. During NAS formation, in particular, the large (extrahepatic) bile ducts become fibrotic and/or necrotic. Patients with NAS may suffer from recurrent jaundice and episodes of cholangitis, and retransplantation may be the only curative treatment. 1 The combination of ischemia and ischemia/ reperfusion (I/R) injury has been shown to be a major Additional supporting information may be found in the online version of this article.

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Section: Discussionmentioning

confidence: 99%

End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

Westerkamp

Mahboub²,

Meyer

et al. 2015

Liver Transpl

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“…Given the complexity and financial burden of a large animal transplantation model, a simulation phase was used to explore our hypothesis, as done previously by other authors (9,10). Innate and adaptive immune responses subsequent to IRI are possible only if all cells are released from compartments such as the spleen, lymph nodes and bone marrow.…”

Section: Discussionmentioning

confidence: 99%

“…These findings are important for several reasons. First, NMP is rapidly becoming the subject of preclinical and clinical research (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Second, different research groups have used various perfusion protocols but none have compared their efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…Normothermic machine perfusion (NMP) is a preservation technology with potential to prevent both ischemic injury and the deleterious effect of cold temperatures by perfusing organs with a warm oxygenated perfusion solution. Numerous studies have demonstrated the advantage of NMP over CS in the preservation of DCD livers (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), suggesting that NMP may greatly benefit the practice of liver transplantation. conducted using whole blood (WB) (9)(10)(11)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

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Comparing Normothermic Machine Perfusion Preservation With Different Perfusates on Porcine Livers From Donors After Circulatory Death

Liu

Nassar

Farias

et al. 2016

American Journal of Transplantation

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The utilization of normothermic machine perfusion (NMP) may be an effective strategy to resuscitate livers from donation after circulatory death (DCD). There is no consensus regarding the efficacy of different perfusates on graft and bile duct viability. The aim of this study was to compare, in an NMP porcine DCD model, the preservation potential of three different perfusates. Twenty porcine livers with 60 min of warm ischemia were separated into four preservation groups: cold storage (CS), NMP with Steen solution (Steen; XVIVO Perfusion Inc., Denver, CO), Steen plus red blood cells (RBCs), or whole blood (WB). All livers were preserved for 10 h and reperfused to simulate transplantation for 24 h. During preservation, the NMP with Steen group presented the highest hepatocellular injury. At reperfusion, the CS group had the lowest bile production and the worst hepatocellular injury compared with all other groups, followed by NMP with Steen; the Steen plus RBC and WB groups presented the best functional and hepatocellular injury outcomes, with WB livers showing lower aspartate aminotransferase release and a trend toward better results for most parameters. Based on our results, a perfusate that contains an oxygen carrier is most effective in a model of NMP porcine DCD livers compared with Steen solution. Specifically, WB-perfused livers showed a trend toward better outcomes compared with Steen plus RBCs.

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“…This period would enable the recovery of the organ as usual, after which it could be transported to a specialized transplantation center, where subsequent recovery of the organ with NELP can occur. The addition of an initial period of SCS prior to NELP, however, has been suggested to negatively impact the viability of these DCD grafts due to their increased sensitivity to cold ischemia (4,5). To assess the feasibility of this hybrid approach, we have evaluated post-operative graft function of orthotopically transplanted ischemic rat livers that were preserved with a combination of cold storage in University of Wisconsin (UW) solution and normothermic Correspondence: Martin L. Yarmush, Shriners Hospital for Children, 51 Blossom Street, Boston, MA 02114, (617)-371-4882, (617)-371-4950 Fax, ireis@sbi.org.…”

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confidence: 99%

Sequential Cold Storage and Normothermic Perfusion of the Ischemic Rat Liver

Tolboom

Milwid

Izamis

et al. 2008

Transplantation Proceedings

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Extending transplant criteria to include livers obtained from donor after cardiac death (DCD) could increase the liver donor pool, but conventional simple cold storage of these ischemic organs can lead to poor graft function after transplantation. Experimental normothermic machine perfusion has previously proven to be useful for the recovery and preservation of DCD livers, but it is more complicated than conventional cold storage, and is therefore perhaps not practical during the entire preservation period. In clinical situations, the combined use of simple cold storage and normothermic perfusion preservation of DCD livers might be more realistic, but even a brief period of cold storage prior to normothermic preservation has been suggested to have a negative impact on graft viability. In this study we show that rat livers subjected to 45 minutes of ex-vivo warm ischemia followed by 2 hours of simple cold storage can be reclaimed by 4 hours of normothermic machine perfusion. These livers could be orthotopically transplanted into syngeneic recipients with 100% survival after 4 weeks (N=10), similar to the survival of animals that received fresh livers that were stored on ice in University of Wisconsin (UW) solution for 6 hours (N=6). On the other hand, rats that received ischemic livers preserved on ice in UW solution for 6 hours (N = 6) all died within 12 hours after transplantation. These results suggest that normothermic perfusion can be used to reclaim DCD livers subjected to an additional period of cold ischemia during hypothermic storage.The current shortage of suitable donor livers could be significantly alleviated by extending liver graft criteria to include livers obtained from donors after cardiac death (DCD). However, conventional with simple cold storage (SCS) of these DCD livers is associated with a higher risk of primary non-function and delayed graft failure (1-3). Normothermic Extracorporeal Liver Perfusion (NELP) has been suggested as an alternative (1-3). However, if machine perfusion of donor organs is to be realized clinically, a brief period of static cold storage between donor organ recovery and normothermic preservation is desirable. This period would enable the recovery of the organ as usual, after which it could be transported to a specialized transplantation center, where subsequent recovery of the organ with NELP can occur. The addition of an initial period of SCS prior to NELP, however, has been suggested to negatively impact the viability of these DCD grafts due to their increased sensitivity to cold ischemia (4,5). To assess the feasibility of this hybrid approach, we have evaluated post-operative graft function of orthotopically transplanted ischemic rat livers that were preserved with a combination of cold storage in University of Wisconsin (UW) solution and normothermic Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscrip...

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Preservation of Porcine Non–heart-Beating Donor Livers by Sequential Cold Storage and Warm Perfusion

Abstract: Normothermic perfusion failed to resuscitate porcine livers after 60 minutes of warm ischemia and 4 hours of cold preservation. Even a short period of cold ischemia is significantly deleterious to the function of ischemically damaged (NHBD) livers.

Cited by 120 publications

References 25 publications

End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

Comparing Normothermic Machine Perfusion Preservation With Different Perfusates on Porcine Livers From Donors After Circulatory Death

Sequential Cold Storage and Normothermic Perfusion of the Ischemic Rat Liver

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