Normothermic Regional Perfusion Research Articles

Machine perfusion in liver transplantation: recent advances and coming challenges.

Machine perfusion has been adopted into clinical practice in Europe since the mid-2010s and, more recently, in the United States (US) following approval of normothermic machine perfusion (NMP). We aim to review recent advances, provide discussion of potential future directions, and summarize challenges currently facing the field. Both NMP and hypothermic-oxygenated perfusion (HOPE) improve overall outcomes after liver transplantation versus traditional static cold storage (SCS) and offer improved logistical flexibility. HOPE offers additional protection to the biliary system stemming from its' protection of mitochondria and lessening of ischemia-reperfusion injury. Normothermic regional perfusion (NRP) is touted to offer similar protective effects on the biliary system, though this has not been studied prospectively.The most critical question remaining is the optimal use cases for each of the three techniques (NMP, HOPE, and NRP), particularly as HOPE and NRP become more available in the US. There are additional questions regarding the most effective criteria for viability assessment and the true economic impact of these techniques. Finally, with each technique purported to allow well tolerated use of riskier grafts, there is an urgent need to define terminology for graft risk, as baseline population differences make comparison of current data challenging. Machine perfusion is now widely available in all western countries and has become an essential tool in liver transplantation. Identification of the ideal technique for each graft, optimization of viability assessment, cost-effectiveness analyses, and proper definition of graft risk are the next steps to maximizing the utility of these powerful tools.

US Liver Transplant Outcomes After Normothermic Regional Perfusion vs Standard Super Rapid Recovery

Normothermic regional perfusion (NRP) is an emerging recovery modality for transplantable allografts from controlled donation after circulatory death (cDCD) donors. In the US, only 11.4% of liver recipients who are transplanted from a deceased donor receive a cDCD liver. NRP has the potential to safely expand the US donor pool with improved transplant outcomes as compared with standard super rapid recovery (SRR). To assess outcomes of US liver transplants using controlled donation after circulatory death livers recovered with normothermic regional perfusion vs standard super rapid recovery. This was a retrospective, observational cohort study comparing liver transplant outcomes from cDCD donors recovered by NRP vs SRR. Outcomes of cDCD liver transplant from January 2017 to May 2023 were collated from 17 US transplant centers and included livers recovered by SRR and NRP (thoracoabdominal NRP [TA-NRP] and abdominal NRP [A-NRP]). Seven transplant centers used NRP, allowing for liver allografts to be transplanted at 17 centers; 10 centers imported livers recovered via NRP from other centers. cDCD livers were recovered by either NRP or SRR. The primary outcome was ischemic cholangiopathy (IC). Secondary end points included primary nonfunction (PNF), early allograft dysfunction (EAD), biliary anastomotic strictures, posttransplant length of stay (LOS), and patient and graft survival. A total of 242 cDCD livers were included in this study: 136 recovered by SRR and 106 recovered by NRP (TA-NRP, 79 and A-NRP, 27). Median (IQR) NRP and SRR donor age was 30.5 (22-44) years and 36 (27-49) years, respectively. Median (IQR) posttransplant LOS was significantly shorter in the NRP cohort (7 [5-11] days vs 10 [7-16] days; P < .001). PNF occurred only in the SRR allografts group (n = 2). EAD was more common in the SRR cohort (123 of 136 [56.1%] vs 77 of 106 [36.4%]; P = .007). Biliary anastomotic strictures were increased 2.8-fold in SRR recipients (7 of 105 [6.7%] vs 30 of 134 [22.4%]; P = .001). Only SRR recipients had IC (0 vs 12 of 133 [9.0%]; P = .002); IC-free survival by Kaplan-Meier was significantly improved in NRP recipients. Patient and graft survival were comparable between cohorts. There was comparable patient and graft survival in liver transplant recipients of cDCD donors recovered by NRP vs SRR, with reduced rates of IC, biliary complications, and EAD in NRP recipients. The feasibility of A-NRP and TA-NRP implementation across multiple US transplant centers supports increasing adoption of NRP to improve organ use, access to transplant, and risk of wait-list mortality.

Normothermic Regional Perfusion to Expand Liver Transplant From Controlled Donation After Circulatory Death

Normothermic Regional Perfusion to Expand Liver Transplant From Controlled Donation After Circulatory Death

(295) - Pediatric Heart Transplantation in Donation After Circulatory Death Using Normothermic Regional Perfusion - Early Experience with Small Donors

(295) - Pediatric Heart Transplantation in Donation After Circulatory Death Using Normothermic Regional Perfusion - Early Experience with Small Donors

(305) - Post-Transplant Survival in Heart Transplantation Using Normothermic Regional Perfusion (NRP) vs. Direct Procurement and Perfusion (DPP) in Donation After Circulatory Determination of Death

(305) - Post-Transplant Survival in Heart Transplantation Using Normothermic Regional Perfusion (NRP) vs. Direct Procurement and Perfusion (DPP) in Donation After Circulatory Determination of Death

(424) - Outcomes with Normothermic Regional Perfusion: Comparison with Core-Cooling During DCD Heart Transplantation

(424) - Outcomes with Normothermic Regional Perfusion: Comparison with Core-Cooling During DCD Heart Transplantation

(231) - Outcomes in Donation After Circulatory Death Cardiac Transplantation Following Direct Procurement and Perfusion Compared with Normothermic Regional Perfusion

(231) - Outcomes in Donation After Circulatory Death Cardiac Transplantation Following Direct Procurement and Perfusion Compared with Normothermic Regional Perfusion

(915) - UK Experience of Direct Procurement of Lungs with Ongoing Abdominal Normothermic Regional Perfusion from Controlled DCD Donors

(915) - UK Experience of Direct Procurement of Lungs with Ongoing Abdominal Normothermic Regional Perfusion from Controlled DCD Donors

Safe and controlled technique of aortic cannulation for thoracoabdominal normothermic regional perfusion

Safe and controlled technique of aortic cannulation for thoracoabdominal normothermic regional perfusion

Ex vivo lung perfusion and the Organ Care System: a review.

With the increasing prevalence of heart failure and end-stage lung disease, there is a sustained interest in expanding the donor pool to alleviate the thoracic organ shortage crisis. Efforts to extend the standard donor criteria and to include donation after circulatory death have been made to increase the availability of suitable organs. Studies have demonstrated that outcomes with extended-criteria donors are comparable to those with standard-criteria donors. Another promising approach to augment the donor pool is the improvement of organ preservation techniques. Both ex vivo lung perfusion (EVLP) for the lungs and the Organ Care System (OCS, TransMedics) for the heart have shown encouraging results in preserving organs and extending ischemia time through the application of normothermic regional perfusion. EVLP has been effective in improving marginal or borderline lungs by preserving and reconditioning them. The use of OCS is associated with excellent short-term outcomes for cardiac allografts and has improved utilization rates of hearts from extended-criteria donors. While both EVLP and OCS have successfully transitioned from research to clinical practice, the costs associated with commercially available systems and consumables must be considered. The ex vivo perfusion platform, which includes both EVLP and OCS, holds the potential for diverse and innovative therapies, thereby transforming the landscape of thoracic organ transplantation.

Stepwise development and expansion of an abdominal normothermic regional perfusion program for donation after circulatory determination of death organ procurement.

Normothermic regional perfusion (NRP) represents an innovative technology that improves the outcomes for liver and kidney recipients of donation after circulatory determination of death (DCD) organs but protocols for abdominal-only NRP (A-NRP) DCD are lacking in the US. We describe the implementation and expansion strategies of a transplant-center-based A-NRP DCD program that has grown in volume, geographical reach, and donor acceptance parameters, presented as four eras. In the implementation era, two donors were attempted, and one liver graft was transplanted. In the local expansion era, 33% of attempted donors resulted in transplantation and 42% of liver grafts from donors who died within the functional warm ischemic time (fWIT) limit were transplanted. In the Regional Expansion era, 25% of attempted donors resulted in transplantation and 50% of liver grafts from donors who died within the fWIT limit were transplanted. In the Donor Acceptance Expansion era, 46% of attempted donors resulted in transplantation and 72% of liver grafts from donors who died within the fWIT limit were transplanted. Eight discarded grafts demonstrated a potential opportunity for utilization. The stepwise approach to building an A-NRP program described here can serve as a model for other transplant centers.

Financial impact of donation after circulatory death heart transplantation: A single-center analysis.

Clinical success of donation after circulatory death (DCD) heart transplantation is leading to growing adoption of this technique. In comparison to procurement from a brain-dead donor, DCD requires additional resources. The economic impact of DCD heart transplantation from the hospital perspective is not well known. We compared the financial data of patients who received DCD allografts to those who received a DBD organ at our institution from January 1, 2021 to December 31, 2022. We also compared the cost of ex-situ machine perfusion to in-situ organ perfusion employed during DCD recovery. We performed 58 DBD and 22 DCD heart-alone transplantations during the study period. Out of 22 DCD grafts, 16 were recovered with thoracoabdominal normothermic regional perfusion (TA-NRP) and six with direct procurement followed by normothermic machine perfusion (DP-NMP). The contribution margin per case for DBD versus DCD was $234,362 and $235,440 (P=.72). The direct costs did not significantly differ between the two groups ($171,949 and 186,250; P=.49). In comparing the two methods of procuring hearts from DCD donors, the direct cost of TA-NRP was $155,955 in comparison to $223,399 for DP-NMP (P=.21). This difference translated into a clinically meaningful but not statistically significant greater contribution margin for TA-NRP ($242, 657vs. $175,768; P=.34). Our data showed that the adoption of DCD procurement did not have a negative financial impact on the contribution margin in our institution. Programs considering starting DCD heart transplantation, and those who are currently performing DCD procurement should evaluate their own financial situation.

Abdominal normothermic regional perfusion in the United States: current state and future directions.

Normothermic regional perfusion (NRP) is a novel procurement technique for donation after circulatory death (DCD) in the United States. It was pioneered by cardiothoracic surgery programs and is now being applied to abdominal-only organ donors by abdominal transplant programs. Liver and kidney transplantation from thoracoabdominal NRP (TA-NRP) donors in the United States was found to have lower rates of delayed kidney graft function and similar graft and patient survival versus recipients of cardiac super rapid recovery (SRR) DCD donors. The excellent outcomes with NRP have prompted the expansion of NRP technology to abdominal transplant programs. Excellent early outcomes with liver and kidney transplantation have prompted the growth of NC-NRP procurement for abdominal-only DCD donors across the US, and now requires standardization of technical and nontechnical aspects of this procedure.

Beyond the Final Heartbeat: Neurological Perspectives on Normothermic Regional Perfusion for Organ Donation after Circulatory Death.

Normothermic regional perfusion (NRP) has recently been used to augment organ donation after circulatory death (DCD) to improve the quantity and quality of transplantable organs. In DCD-NRP, after withdrawal of life-sustaining therapies and cardiopulmonary arrest, patients are cannulated onto extracorporeal membrane oxygenation to reestablish blood flow to targeted organs including the heart. During this process, aortic arch vessels are ligated to restrict cerebral blood flow. We review ethical challenges including whether the brain is sufficiently reperfused through collateral circulation to allow reemergence of consciousness or pain perception, whether resumption of cardiac activity nullifies the patient's prior death determination, and whether specific authorization for DCD-NRP is required. ANN NEUROL 2024.

Thoraco-abdominal normothermic regional perfusion for thoracic transplantation in the United States: current state and future directions.

To provide an update regarding the state of thoracoabdominal normothermic regional perfusion (taNRP) when used for thoracic organ recovery. taNRP is growing in its utilization for thoracic organ recovery from donation after circulatory death donors, partly because of its cost effectiveness. taNRP has been shown to yield cardiac allograft recipient outcomes similar to those of brain-dead donors. Regarding the use of taNRP to recover donor lungs, United Network for Organ Sharing (UNOS) analysis shows that taNRP recovered lungs are noninferior, and taNRP has been used to consistently recover excellent lungs at high volume centers. Despite its growth, ethical debate regarding taNRP continues, though clinical data now supports the notion that there is no meaningful brain perfusion after clamping the aortic arch vessels. taNRP is an excellent method for recovering both heart and lungs from donation after circulatory death donors and yields satisfactory recipient outcomes in a cost-effective manner. taNRP is now endorsed by the American Society of Transplant Surgeons, though ethical debate continues.

Sequential Normothermic Regional Perfusion and End-ischemic Ex Situ Machine Perfusion Allow the Safe Use of Very Old DCD Donors in Liver Transplantation.

In Italy, 20 min of continuous, flat-line electrocardiogram are required for death declaration. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death (cDCD) liver transplantation by combining normothermic regional and end-ischemic machine perfusion (MP). The aim of this study was to evaluate the safety and feasibility of the use of septuagenarian and octogenarian cDCD donors with this approach. All cDCD older than 70 y were evaluated during normothermic regional perfusion and then randomly assigned to dual hypothermic or normothermic MP. In the period from April 2021 to December 2022, 17 cDCD older than 70 y were considered. In 6 cases (35%), the graft was not considered suitable for liver transplantation, whereas 11 (65%) were evaluated and eventually transplanted. The median donor age was 82 y, being 8 (73%) older than 80. Median functional warm ischemia and no-flow time were 36 and 28 min, respectively. Grafts were randomly assigned to ex situ dual hypothermic oxygenated MP in 6 cases (55%) and normothermic MP in 5 (45%). None was discarded during MP. There were no cases of primary nonfunction, 1 case of postreperfusion syndrome (9%) and 2 cases (18%) of early allograft dysfunction. At a median follow-up of 8 mo, no vascular complications or ischemic cholangiopathy were reported. No major differences were found in terms of postoperative hospitalization or complications based on the type of MP. The implementation of sequential normothermic regional and end-ischemic MP allows the safe use of very old donation after circulatory death donors.

Normothermic regional perfusion procurement for abdominal organ donors: techniques and troubleshooting.

Normothermic regional perfusion (NRP) is a novel procurement technique for donation after circulatory death (DCD) in the United States. It was pioneered by cardiothoracic surgery programs and is now being applied to abdominal-only organ donors by abdominal transplant programs. Multiple technical approaches can be used for abdominal-only NRP DCD donors and this review describes these techniques. NRP has been associated with higher utilization of organs, particularly liver and heart grafts, from DCD donors and with better recipient outcomes. There are lower rates of delayed graft function in kidney transplant recipients and lower rates of ischemic cholangiopathy in liver transplant recipients. These benefits are driving increased interest from abdominal transplant programs in using NRP for DCD procurements. This paper describes the technical aspects of NRP DCD that allow for maximization of its use based on different donor and policy characteristics.

Intraoperative Anesthetic Strategies to Mitigate Early Allograft Dysfunction After Orthotopic Liver Transplantation: A Narrative Review.

Orthotopic liver transplantation (OLT) is the most effective treatment for patients with end-stage liver disease (ESLD). Hepatic insufficiency within a week of OLT, termed early allograft dysfunction (EAD), occurs in 20% to 25% of deceased donor OLT recipients and is associated with morbidity and mortality. Primary nonfunction (PNF), the most severe form of EAD, leads to death or retransplantation within 7 days. The etiology of EAD is multifactorial, including donor, recipient, and surgery-related factors, and largely driven by ischemia-reperfusion injury (IRI). IRI is an immunologic phenomenon characterized by dysregulation of cellular oxygen homeostasis and innate immune defenses in the allograft after temporary cessation (ischemia) and later restoration (reperfusion) of oxygen-rich blood flow. The rising global demand for OLT may lead to the use of marginal allografts, which are more susceptible to IRI, and thus lead to an increased incidence of EAD. It is thus imperative the anesthesiologist is knowledgeable about EAD, namely its pathophysiology and intraoperative strategies to mitigate its impact. Intraoperative strategies can be classified by 3 phases, specifically donor allograft procurement, storage, and recipient reperfusion. During procurement, the anesthesiologist can use pharmacologic preconditioning with volatile anesthetics, consider preharvest hyperoxemia, and attenuate the use of norepinephrine as able. The anesthesiologist can advocate for normothermic regional perfusion (NRP) and machine perfusion during allograft storage at their institution. During recipient reperfusion, the anesthesiologist can optimize oxygen exposure, consider adjunct anesthetics with antioxidant-like properties, and administer supplemental magnesium. Unfortunately, there is either mixed, little, or no data to support the routine use of many free radical scavengers. Given the sparse, limited, or at times conflicting evidence supporting some of these strategies, there are ample opportunities for more research to find intraoperative anesthetic strategies to mitigate the impact of EAD and improve postoperative outcomes in OLT recipients.

Should advanced perfusion be the standard of care for donation after circulatory death liver transplant?

As an alternative to static cold storage (SCS), advanced perfusion techniques such as normothermic regional perfusion and ex-situ perfusion (normothermic or hypothermic) have emerged as a way to improve the ischemic injury suffered by donation after circulatory death (DCD) livers. Multiple studies have been published that have demonstrated superior post-DCD liver transplant outcomes when using advanced perfusion compared with SCS. In particular, these studies have shown lower rates of ischemic cholangiopathy with advanced perfusion. In addition to the improved post-liver transplant outcomes, studies have also demonstrated higher rates of liver utilization from DCD donors when advanced perfusion is used compared with SCS. Given the high rates of graft loss in patients who develop ischemic cholangiopathy, the significant reduction seen in DCD donor livers that have undergone advanced perfusion represents a key step in more broad utilization of these livers. With such compelling evidence from multiple trials, it seems reasonable to ask the question: should advanced perfusion be the standard of care for DCD liver transplant?

Association of procurement technique with organ yield and cost following donation after circulatory death

Donation after circulatory death (DCD) could account for the largest expansion of the donor allograft pool in the contemporary era. However, the organ yield and associated costs of normothermic regional perfusion (NRP) compared to super-rapid recovery (SRR) with ex-situ normothermic machine perfusion, remain unreported. The Organ Procurement and Transplantation Network (December 2019 to June 2023) was analyzed to determine the number of organs recovered per donor. A cost analysis was performed based on our institution’s experience since 2022. Of 43 502 donors, 30 646 (70%) were donors after brain death (DBD), 12 536 (29%) DCD-SRR and 320 (0.7%) DCD-NRP. The mean number of organs recovered was 3.70 for DBD, 3.71 for DCD-NRP (P < .001), and 2.45 for DCD-SRR (P < .001). Following risk adjustment, DCD-NRP (adjusted odds ratio 1.34, confidence interval 1.04-1.75) and DCD-SRR (adjusted odds ratio 2.11, confidence interval 2.01-2.21; reference: DBD) remained associated with greater odds of allograft nonuse. Including incomplete and completed procurement runs, the total average cost of DCD-NRP was $9463.22 per donor. By conservative estimates, we found that approximately 31 donor allografts could be procured using DCD-NRP for the cost equivalent of 1 allograft procured via DCD-SRR with ex-situ normothermic machine perfusion. In conclusion, DCD-SRR procurements were associated with the lowest organ yield compared to other procurement methods. To facilitate broader adoption of DCD procurement, a comprehensive understanding of the trade-offs inherent in each technique is imperative.