Industry Literature

Preservation for heart transplantation is actively evolving. Stay abreast of the news with this simple resource for recent publications. The following industry specific literature citations are selected for the content of donor heart preservation and perfusion.

Game changers: At the forefront of organ perfusion technology April 15, 2019

INSIGHTS

Game changers

Companies at the forefront of organ perfusion technology

“We work on the lungs like a team works on a patient.”

Martine Rothblatt, PhD, Chairman & CEO, United Therapeutics

Lung Bioengineering

Toronto EVLP System (IDE for clinical trial lungs)
XVIVO XPS (HDE for non-trial lungs)

Company headquarters: Silver Spring, Maryland

Organ: Lung

Current clinical trials: FDA approval received for Phase 3 trial for 16 centers and 93, or fewer, EVLP transplants.

Company website

One significant challenge to widespread implementation of NMP is having the technology and skilled clinical specialists available when needed. Lung Bioengineering, a United Therapeutics subsidiary, seeks to address this challenge with freestanding, centralized perfusion facilities staffed around the clock, to serve multiple transplant centers. Initially unacceptable/marginal lungs are transported to the facility and perfused.

Real-time HD monitoring allows the transplant team to examine the lung remotely during perfusion; if deemed acceptable, the lung is returned to the transplant center. “We work on the lungs like a team works on a patient,” notes United Therapeutics’ Chairman and CEO Martine Rothblatt, PhD. She says during the Phase 2 clinical trial, about two-thirds of the initially unacceptable lungs received by the center were recovered, accepted and successfully transplanted, with perfusion performed on the Toronto EVLP System technology developed at University Health Network in Toronto, Canada. (Lung perfusion services are also available for transplant centers not participating in the trial, with the XVIVO XPS device under the FDA’s HDE approval.)

“Ultimately our goal is to ramp up the availability of lungs for transplant,” says Rothblatt; the company hopes to establish four perfusion centers nationwide with the goal of doubling the number of lung transplants performed annually in the US.

An EVLP Suite

Lung Bioengineering’s headquarters in Silver Spring, Maryland

“Ideally speaking, every organ that is salvageable that has the potential to be transplanted should be assessed and should be allowed time on perfusion technology without impact of ischemia and cold static preservation.”

Tamer Khayal, M.D., Chief Commercial Officer, TransMedics

TransMedics Inc.

Organ Care System (OCS™) Transportable NMP

Company headquarters: Andover, Massachusetts

Organ: Lung, heart, liver

FDA status: PMA for OCS lung, IDE – EA for OCS heart, IDE for OCS liver

Current clinical trials:

  • U.S. OCS Heart EXPAND
  • U.S. The Organ Care System (OCS™) Lung Thoracic Organ Perfusion (TOP) Post Approval Study (PAS) Registry – OCS™ Lung TOP PAS Registry
  • International OCS Lung EXPAND
  • International OCS Liver PROTECT

Company website

The OCS Lung is currently “the only PMA approved medical technology for ex-vivo perfusion and assessment for routine donor/standard criteria lung transplants in the US,” says TransMedics Chief Commercial Officer Tamer Khayal, M.D. The OCS—which the company has developed for lung, liver, and heart transplantations—is a portable device for NMP that makes it possible to perform perfusion continuously from donor recovery to recipient.

OCS devices were designed to minimize ischemic injury, in comparison to static cold storage preservation. The OCS also allows for diagnostic monitoring of organ viability or function and therapeutic or optimization capabilities during perfusion.

The TransMedics vision is that “ideally speaking, every organ that is salvageable that has the potential to be transplanted should be assessed and should be allowed time on perfusion technology without impact of ischemia and cold static preservation,” says Khayal.

To date, OCS devices have been used in nearly 1,200 transplants worldwide.

“Risk and urgency are the two areas we are tackling head-on with this technology.”

Craig Marshall, CEO, OrganOx

OrganOx

metra®

Company headquarters: Oxford, England

Organ: Liver

FDA status: Clinical trial IDE

Current clinical trials: U.S. OrganOx metra®

Company website

“Risk and urgency are the two areas we are tackling head-on with this technology,” says OrganOx CEO Craig Marshall.

The metra® (pronounced meetra, from the Greek for womb) is a transportable normothermic machine perfusion (NMP) device that is now in a multi-center Investigational device exemption (IDE) clinical trial in the U.S. comparing the safety and efficacy of preservation and transport on the device to conventional static cold storage (SCS).

“By making it possible to assess the liver ex vivo, we are attempting to reduce the risk associated with lack of information about an organ,” says Marshall. And with clinical data from Europe indicating that livers can be perfused safely for up to 24 hours on the metra®, the device, Marshall says, benefits transplant surgery teams and recipients alike by reducing the urgency of the critical time limits imposed by SCS.

Surgeons David Nasralla and Annemarie Weissenbacher inspecting a liver perfusing on the OrganOx metra® device

“We can offer an additional tool in the clinician’s toolbox to assess lungs that might previously have not been utilized.”

Dan Martinelli, Head of Sales America, XVIVO Perfusion

XVIVO Perfusion

XPS

Company headquarters: Gothenburg, Sweden

Organ: Lung

FDA status: HDE “for flushing and temporary continuous normothermic perfusion of initially unacceptable excised donor lungs.”

Current clinical trials: None

Company website

Directed by the company’s vision “that nobody should have to die waiting for an organ,” XVIVO focuses on expanding the use of ex vivo lung perfusion to increase the number of transplantable lungs, says XVIVO Head of Sales Dan Martinelli.

In the completed NOVEL clinical trial, initially unacceptable extended criteria/marginal donor lungs were assessed for transplant via NMP on the XPS device.

Before perfusion, “the majority of those lungs were turned down by the majority of the transplant centers” enrolled in the trial, says Martinelli. Those found acceptable following perfusion and active evaluation, however, were successfully transplanted and demonstrated outcomes—including three-year survival rates—comparable to standard criteria lungs.

“It is the first trial in the U.S. that specifically looked at marginal lungs” and resulted in the FDA’s HDE approval for the XPS, notes XVIVO clinical research program manager Jaya Tiwari. Now, says Martinelli, the XPS can offer “an additional tool in the clinician’s toolbox” to assess lungs that might previously have not been utilized.

Photos courtesy of XVIVO Perfusion

Learn more

ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world.

FDA Terms

The post appeared first on UNOS.

Importance of a Partnered Heart Failure Network to Increase Access to Advanced Heart Failure Therapies April 1, 2019

Our hypothesis is that by improving access to advanced heart failure specialists (AHFS) through partnered outreach clinics, we can increase the number of patients benefitted by advanced heart failure (AHF) therapies delivered at our center. This partnered network approach can potentially overcome distance barriers, optimize referral timing, and expedite access to AHFS from the regional center of excellence.

Does Donor-Recipient Age Difference Matter in the Outcome of Heart Transplantation? April 1, 2019

With the growing shortage of organ donors, marginal donor organs are increasingly accepted, which may partially explain the continued increase in donor age. The potential interactions between donor-recipient (D/R) age difference and outcomes after heart transplantation (HT) are not well known, and organ allocation systems do not routinely consider D/R age matching. We thus aimed to study the impact of D/R age difference on HT outcomes.

Bioengineering approaches to organ preservation ex vivo. March 19, 2019
Related Articles

Exp Biol Med (Maywood). 2019 Mar 19;:1535370219834498

Authors: Pinezich M, Vunjak-Novakovic G

Abstract
IMPACT STATEMENT: Over the past several decades, ex vivo perfusion has emerged as a promising technology for the assessment, preservation, and recovery of donor organs. Many exciting pre-clinical findings have now been translated to clinical use, and successful transplantation following ex vivo perfusion has been achieved for heart, lung, and liver. While machine perfusion provides distinct advantages over traditional cold preservation, many challenges remain, including that of long-term (multi-day) ex vivo support. Here, we provide an overview of the current status of ex vivo machine perfusion in the pre-clinical and clinical setting and share our perspective on the future direction of the field.

PMID: 30889963 [PubMed – as supplied by publisher]

Myocardial functional decline during prolonged ex situ heart perfusion. March 11, 2019
Related Articles

Ann Thorac Surg. 2019 Mar 11;:

Authors: Hatami S, White CW, Shan S, Haromy A, Qi X, Ondrus M, Kinnear A, Himmat S, Michelakis E, Nagendran J, Freed DH

Abstract
BACKGROUND: Myocardial function declines in a time dependent fashion during ex situ heart perfusion. Cell death and metabolic alterations may contribute to this phenomenon, limiting the safe perfusion period and the potential of ex situ heart perfusion to expand the donor pool. Our aim is to investigate the etiology of myocardial functional decline in ex situ perfused hearts.
METHODS: Cardiac function, apoptosis, effectors and markers of cell death, and metabolic function were assessed in healthy pig hearts, perfused for 12 hours. These hearts were perfused either in non-working mode (NWM), or working mode (WM).
RESULTS: Cardiac function declined during ex situ heart perfusion regardless of perfusion mode but was significantly better preserved in the hearts perfused in WM (11-hour cardiac index / 1-hour cardiac index: WM=33 vs. NWM=10%, p=0.025). The rate of apoptosis was higher in the ex situ perfused hearts compared to in vivo samples (% apoptotic cells: in vivo=0.13, WM=0.54, NWM=0.88%, p<0.001) but the absolute values were low and out of proportion to the decline in function in either group. Myocardial dysfunction at the end of the perfusion interval was partially rescued by delivery of a pyruvate bolus.
CONCLUSIONS: Hearts preserved ex situ experience a significant decline in myocardial function over time that is out of proportion to the magnitude of myocyte cell death present in dysfunctional hearts. Alterations in myocardial substrate utilization during prolonged ex situ heart perfusion may contribute to this phenomenon, and represent an avenue to improve donor heart preservation.

PMID: 30872100 [PubMed – as supplied by publisher]

Primary Graft Dysfunction: Worry Less about Organ Quality and Do More to Improve Candidate Condition March 10, 2019

In this issue of the Journal, Profita and colleagues report findings from a well-controlled analysis matching outcomes from the Organ Procurement and Transplantation Network (OPTN) and the Extracorporeal Life Support Organization (ELSO) datasets to identify incidences of and risk factors for severe primary graft dysfunction (PGD) in pediatric heart transplant recipients within the United States.1 The authors find no change in the incidence of severe PGD across two decades of pediatric heart transplant.

An integrated molecular diagnostic report for heart transplant biopsies using an ensemble of diagnostic algorithms February 5, 2019

We previously reported a microarray-based diagnostic system for heart transplant endomyocardial biopsies (EMBs), using either 3-archetype (3AA) or 4-archetype (4AA) unsupervised algorithms to estimate rejection. The present study aimed to examine the stability of machine-learning algorithms in new biopsies, compare 3AA vs. 4AA algorithms, assess supervised binary classifiers trained on histologic or molecular diagnoses, create a report combining many scores into an ensemble of estimates, and examine possible automated sign-outs.

Creating the first national donor image sharing hub February 5, 2019

Pilot project tests new system that could offer quick access to high-quality medical images and facilitate more transplants

By Judy Ivey

Rob McTier, United Network for Organ Sharing

UNOS business architect Rob Mctier (standing) working with the technology development team.

A medical image sharing pilot project underway now at UNOS may soon give organ procurement organizations, and donor and transplant hospitals universal access to high-quality medical imaging studies during the organ offer process. Creating a consistent, reliable and secure national image sharing system has the potential to decrease the number of organs that are not used and increase the number of transplants overall.

How image sharing often happens now

When the procurement team at Baltimore-based Living Legacy Foundation of Maryland needs images of a donor’s organs, they often take them with their iPhones. The OPO has more than 150 donors each year.

The images are emailed or sent via text to Living Legacy’s communications center and then shared with surgeons who request them explains Debbi McRann, Chief Clinical Officer. “But the quality isn’t good and we can’t upload it to DonorNet® because the file is too big. We’re only giving surgeons a partial scan because of the limitations.”

DonorNet® currently accommodates certain images as attachments, but file sizes are limited and the process of acquiring and attaching images is inefficient, preventing routine use.
When surgeons can’t clearly see the organ being offered, given the risk of travel to recover and the possibility that the organ won’t meet their patient’s needs when they see it in person, it stands to reason that they would hesitate to accept some offers. This results in unused organs that could otherwise help save patients’ lives.

“Another one of the challenges we’ve been having when we receive offers from outside centers is that they will have multiple donors listed, so the risk is it’s not linked to the actual donor record so you could potentially download the wrong CT and send it to the surgeon,” explains McRann.

The pilot includes functionality that addresses this risk. When an OPO uploads an imaging study, DonorNet® compares the patient name, gender, and date of birth on the imaging study with the donor name, gender, and date of birth in DonorNet®. If there are differences, DonorNet® warns the OPO user and allows the OPO user to resolve the conflicting data before displaying the imaging study to transplant hospital users.

While some OPOs use image sharing systems, the existing process can be costly, involving multiple vendors and external applications that don’t necessarily talk with each other.

The pilot project currently underway could make a high quality universal donor image system a reality.
UNOS is partnering with New York City-based image sharing provider Ambra Health and six OPOs around the country to test a solution that would make available large file-size medical images, radiographs, videos of echocardiograms, catheterizations, pulmonary bronchoscopies, and other images to OPOs, and transplant and donor hospitals.

“If we can have a consistent way for everyone to transfer information, that’s going to decrease errors,” says McRann. “Right now, there are many different ways of showing these images. If there were only one, there’d be more standardization and fewer errors” and surgeons could decide to transplant organs they may not have considered otherwise.

Target solution

“This pilot is just the first step,” says UNOS business architect Rob McTier who helms the seven-member team that has spent the last several years developing the system. “We want to be able to provide an infrastructure that will enable the sharing of this information.”

“Donor imaging helps other programs learn from each other,” says Jared Sierkierka, Clinical Operations Manager for Donor Network West, based in San Ramon, California, which adopted an image sharing system in 2011. “Transplant hospitals can look at the causes of hesitation when an organ is declined. Other organizations will look at why others accepted an organ they declined and learn.”

How it works

During the pilot, OPOs receive high-quality imaging studies on CDs or thumb-drives. They login to DonorNet® with their existing username and password to upload the imaging study similar to the way they upload smaller attachments. DonorNet® links the imaging studies to a specific donor’s record in DonorNet®. Transplant hospitals login to DonorNet® with their existing username and password to view the imaging study using a DICOM viewing tool.

If the pilot is successful, the national system could work like this:

  • The OPO requests an imaging study for a donor from a donor hospital.
  • The donor hospital sends the imaging study to UNOS’s imaging hub.
  • DonorNet® will automatically connect the imaging study to the appropriate donor record.
  • Both the OPO and transplant hospital will log in to DonorNet® and be able to view the imaging study using a DICOM viewing tool.

“I was amazed when I saw the images,” says Dr. Daniel Jacoby, Director of the Comprehensive Heart Failure Program at Yale School of Medicine and founder and director of Yale’s cardiomyopathy program who tested the system. “They look like you’re looking directly at an echo screen. This is a step forward for our patients.”

Says McRann, “I think, because they’re connected right to the donor record, more surgeons and coordinators will be able to look at the images faster and make their decisions faster. This can speed up allocation.”

What’s next

If the pilot is successful, McTier says UNOS plans to make the system available nationwide. Over the next few months, look for updates on UNOS.org about the pilot, including a Q&A with the development team.

Read more about the pilot and for information about available education resources for participating OPOs.

OPOs participating in the pilot

  • Center for Organ Recovery and Education, Pittsburgh, PA
  • Donor Network West, San Ramon, CA
  • Lifesharing: A Donate Life Organization, San Diego, CA
  • LifeQuest Organ Recovery Services, Gainesville, FL
  • Nevada Donor Network, Las Vegas, NV
  • One Legacy, Los Angeles, CA

The post appeared first on UNOS.

Incidence, predictors, and outcomes after severe primary graft dysfunction in pediatric heart transplant recipients January 23, 2019

Previous reports of primary graft dysfunction (PGD) in pediatric heart transplant (HT) recipients are limited to descriptive series of children who required extracorporeal membrane oxygenation (ECMO) support shortly after HT. In this study we sought to determine the incidence, risk factors, and survival after severe PGD in pediatric HT recipients.

Data definition process in place to bring clarity and consistency to transplant forms January 15, 2019

Audience

All UNetSM users who complete OPTN data collection forms

Implementation

January 15, 2019; quarterly updates

At-a-glance

A cross-functional team of UNOS staff and OPTN members is working on a data governance initiative to improve the consistency and quality of OPTN data collection. The first set of data definitions using a new format are published in UNet online Help as of January 15, 2019.

We will provide a list of revised definitions each quarter, to answer member questions about existing data fields and to clarify new requirements.

More details

This effort aims to provide clear, concise data definitions, improve quality of data, and provide transparency into changes. Clarifications are intended to provide guidance for future data entry; you are not required to amend data submitted before the collection date. The process to create revised data definitions includes reviews by multidisciplinary UNOS staff and the Data Advisory Committee.

Summary of definition changes

Data Element System Form Description
Gender TIEDI®
DonorNet®
KPDSM
DDR and LDR
DNR
Add/Edit Donor
Intent is to collect biologic and physiologic traits (sex) at birth.
Total Cold Ischemic Time TIEDI® Liver TRR Cold ischemic time starts when the organ is cross-clamped and ends when it is first perfused with warm recipient blood (i.e. first clamp removed in situ). Previous to this change, the hepatic artery and portal vein clamps both had to be removed before ischemic time ended.
Prior Cardiac Surgery (non-transplant) TIEDI® Heart, Lung and Heart-Lung TCR VAD should be included in the report of previous cardiac surgeries.
Time of implant/initiation WaitlistSM Adult Heart Status Justification Form New data collection element released, initial definition established with implementation of heart allocation policy on 10/18/2018.
Patient Using Either Oral Medication or Diet for Blood Sugar Control TIEDI® Pancreas and Kidney-Pancreas TRR and TRF Any anti-hyperglycemic medications should be listed in this field, including oral and non-insulin injectables.

Where to find the info in Help Documentation

Access Secure Enterprise and then choose TIEDI. On the menu, choose Help and click Online Help. Details can be found under Manage Data – Data Definitions and History of Definition Changes. Record Field Descriptions have also been updated to include each data element.

Background

The OPTN’s secure transplant information database contains all national data on the candidate waiting list, organ donation and matching, and transplantation. Organ transplant institutions use the system to match waiting candidates with donated organs. Institutions also rely on the database to manage time-sensitive, life-critical data, before and after their patients’ transplants.

Contact

If you have questions, please contact UNOS Customer Service at (800) 978-4334 or unethelpdesk@unos.org.

Normothermic Ex Situ Heart Perfusion in Working Mode: Assessment of Cardiac Function and Metabolism. January 12, 2019

J Vis Exp. 2019 Jan 12;(143):

Authors: Hatami S, White CW, Ondrus M, Qi X, Buchko M, Himmat S, Lin L, Cameron K, Nobes D, Chung HJ, Nagendran J, Freed DH

Abstract
The current standard method for organ preservation (cold storage, CS), exposes the heart to a period of cold ischemia that limits the safe preservation time and increases the risk of adverse post-transplantation outcomes. Moreover, the static nature of CS does not allow for organ evaluation or intervention during the preservation interval. Normothermic ex situ heart perfusion (ESHP) is a novel method for preservation of the donated heart that minimizes cold ischemia by providing oxygenated, nutrient-rich perfusate to the heart. ESHP has been shown to be non-inferior to CS in the preservation of standard-criteria donor hearts and has also facilitated the clinical transplantation of the hearts donated after the circulatory determination of death. Currently, the only available clinical ESHP device perfuses the heart in an unloaded, non-working state, limiting assessments of myocardial performance. Conversely, ESHP in working mode provides the opportunity for comprehensive evaluation of cardiac performance by assessment of functional and metabolic parameters under physiologic conditions. Moreover, earlier experimental studies have suggested that ESHP in working mode may result in improved functional preservation. Here, we describe the protocol for ex situ perfusion of the heart in a large mammal (porcine) model, which is reproducible for different animal models and heart sizes. The software program in this ESHP apparatus allows for real-time and automated control of the pump speed to maintain desired aortic and left atrial pressure and evaluates a variety of functional and electrophysiological parameters with minimal need for supervision/manipulation.

PMID: 30688296 [PubMed – in process]

Cardiac Allograft Vasculopathy and Graft Failure in Pediatric Heart Transplant Recipients After Rejection with Severe Hemodynamic Compromise December 19, 2018

Rejection with severe hemodynamic compromise (RSHC) carries a mortality risk approaching 50%. We aimed to identify current risk factors for RSHC and predictors of graft failure after RSHC.

Exosomal profiling in cardiac allograft rejection: Best basic science article in 2018. December 19, 2018

Identifying patients who are at risk for complications after thoracic transplantation assists in better defining outcomes and promoting discovery of new mechanisms that can be targeted to mitigate these complications. The gold-standard for diagnosing rejection, a major cause of morbidity and mortality after transplantation, is biopsy, which (1) is not risk-free, (2) may not be practical in critically ill patients and (3) may result in false-negative findings.1 Exosomes had been described as far back as in 1981 as membrane fragments from reticulocytes detected in body fluids.

Sizing it Up in Heart Transplantation: Time to Change the Guidelines? December 13, 2018

It’s not the size of a man, but the size of his heart that matters.Evander Holyfield, American professional boxer (1962-)

Utilization of organs to pediatric heart transplant recipients December 13, 2018

While survival after pediatric heart transplantation (pHT) has improved in the past few decades and mechanical circulatory support is increasingly used to bridge children to transplantation, waiting list deaths remain a stark reality. To increase the donor pool, strategies such as ABO-incompatible transplantation or donation after cardiac death (DCD) have been attempted.1,2 The real question we have to ask is whether the current donor pool offers are appropriately being used. The article by Davies and colleagues in this issue of the journal looked at the rate of declines in donor offers for pediatric recipients and their consequences.

Hypothermic perfusion of donor heart with a preservation solution supplemented by mesenchymal stem cells December 6, 2018

Heart transplantation is the definitive treatment for end-stage heart failure. A shortage of donor hearts forced transplant programs to accept older donors and longer ischemic times. Previous studies have suggested that administration of mesenchymal stem cells (MSCs) or their conditioned medium (CM) protects the heart against ischemia/reperfusion injury (IRI). We hypothesized that the preservation of donor hearts with a CM would protect the graft from IRI after prolonged storage in 15-month-old rats and investigated mRNA changes attributable to CM.

Consistent success in life-supporting porcine cardiac xenotransplantation. December 5, 2018
Related Articles

Nature. 2018 Dec 05;:

Authors: Längin M, Mayr T, Reichart B, Michel S, Buchholz S, Guethoff S, Dashkevich A, Baehr A, Egerer S, Bauer A, Mihalj M, Panelli A, Issl L, Ying J, Fresch AK, Buttgereit I, Mokelke M, Radan J, Werner F, Lutzmann I, Steen S, Sjöberg T, Paskevicius A, Qiuming L, Sfriso R, Rieben R, Dahlhoff M, Kessler B, Kemter E, Klett K, Hinkel R, Kupatt C, Falkenau A, Reu S, Ellgass R, Herzog R, Binder U, Wich G, Skerra A, Ayares D, Kind A, Schönmann U, Kaup FJ, Hagl C, Wolf E, Klymiuk N, Brenner P, Abicht JM

Abstract
Heart transplantation is the only cure for patients with terminal cardiac failure, but the supply of allogeneic donor organs falls far short of the clinical need1-3. Xenotransplantation of genetically modified pig hearts has been discussed as a potential alternative4. Genetically multi-modified pig hearts that lack galactose-α1,3-galactose epitopes (α1,3-galactosyltransferase knockout) and express a human membrane cofactor protein (CD46) and human thrombomodulin have survived for up to 945 days after heterotopic abdominal transplantation in baboons5. This model demonstrated long-term acceptance of discordant xenografts with safe immunosuppression but did not predict their life-supporting function. Despite 25 years of extensive research, the maximum survival of a baboon after heart replacement with a porcine xenograft was only 57 days and this was achieved, to our knowledge, only once6. Here we show that α1,3-galactosyltransferase-knockout pig hearts that express human CD46 and thrombomodulin require non-ischaemic preservation with continuous perfusion and control of post-transplantation growth to ensure long-term orthotopic function of the xenograft in baboons, the most stringent preclinical xenotransplantation model. Consistent life-supporting function of xenografted hearts for up to 195 days is a milestone on the way to clinical cardiac xenotransplantation7.

PMID: 30518863 [PubMed – as supplied by publisher]

Utilization of the organ care system – a game-changer in combating donor organ shortage. November 18, 2018
Icon for PubMed Central Related Articles

Utilization of the organ care system – a game-changer in combating donor organ shortage.

Med Sci Monit Basic Res. 2015 Mar 12;21:29-32

Authors: Popov AF, García Sáez D, Sabashnikov A, Patil NP, Zeriouh M, Mohite PN, Zych B, Schmack B, Ruhparwar A, Kallenbach K, Dohmen PM, Karck M, Simon AR, Weymann A

Abstract
For patients with end-stage heart failure, cardiac transplantation persists to be the gold standard. Nevertheless, the availability of organs remains a main constraint to the treatment. Through mounting usage of ex vivo heart perfusion an increase in organ availability was achieved by reconditioning of organs formerly not regarded as appropriate for transplantation. We propose the future standard application of this state-of-the-art technology to improve the pool of donor organs by evaluating hearts outside standard acceptability criteria.

PMID: 25761708 [PubMed – indexed for MEDLINE]

Successful transplantation in canines after long-term coronary sinus machine perfusion preservation of donor hearts. November 18, 2018
Icon for Elsevier Science Related Articles

Successful transplantation in canines after long-term coronary sinus machine perfusion preservation of donor hearts.

J Heart Lung Transplant. 2016 08;35(8):1031-6

Authors: Brant S, Holmes C, Cobert M, Powell L, Shelton J, Jessen M, Peltz M

Abstract
BACKGROUND: Machine perfusion is a promising strategy for donor heart preservation, but delivery of perfusate through the aorta may be limited by aortic valve incompetence. We hypothesized that retrograde machine perfusion preservation through the coronary sinus avoided this issue and allowed for recovery of donor hearts after long-term storage.
METHODS: Canine hearts were procured after arrest with 1 liter University of Wisconsin Machine Perfusion Solution (UWMPS) and preserved for 14 hours by static hypothermic storage (Static group, n = 5) or retrograde machine perfusion through the coronary sinus (RP group, n = 5). Myocardial oxygen consumption (MVo2) and lactate were monitored in perfused hearts. Hearts were implanted and reperfused for 6 hours. The pre-load recruitable stroke work was determined as a measure of myocardial function. Cardiac enzyme release was quantified. Cell death was evaluated by TUNEL (terminal deoxynucleotidyltransferase-mediated deoxy uridine triphosphate nick-end label).
RESULTS: MVo2 decreased initially then stabilized. Lactate accumulation was low in RP hearts. All RP hearts separated from cardiopulmonary bypass. All Static hearts required a return to bypass (p < .05). Pre-load recruitable stroke work in RP hearts was increased (55 ± 7 mm Hg) compared with Static (20 ± 11 mm Hg, p < .05) and did not differ from baseline values. Creatine kinase release was greater in Static group hearts (102 ± 16 IU/liter/g) than in RP hearts (51 ± 8 IU/liter/g, p < .05). The fraction of TUNEL-positive cells was higher in the Static group, but this difference was not significant.
CONCLUSIONS: Retrograde machine perfusion can preserve donor hearts for long intervals. Cardiac function after implantation suggested excellent myocardial protection. Retrograde machine perfusion appears promising for extending the donor ischemic interval and improving results of heart transplantation.

PMID: 27160493 [PubMed – indexed for MEDLINE]

Moderate hypothermia during ex vivo machine perfusion promotes recovery of hearts donated after cardiocirculatory death†. November 18, 2018
Icon for Silverchair Information Systems Related Articles

Moderate hypothermia during ex vivo machine perfusion promotes recovery of hearts donated after cardiocirculatory death†.

Eur J Cardiothorac Surg. 2016 Jan;49(1):25-31

Authors: Tolboom H, Olejníčková V, Reser D, Rosser B, Wilhelm MJ, Gassmann M, Bogdanova A, Falk V

Abstract
OBJECTIVES: To establish the optimal machine perfusion temperature for recovery of hearts in a rodent model of donation after declaration of cardiocirculatory death (DCD).
METHODS: Hearts from male Lewis rats (n = 14/group) were subjected to 25 min of in situ warm (37°C) ischaemia to simulate DCD. They were then explanted and reperfused with diluted autologous blood for 60 min at 20, 25, 30, 33 or 37°C, after which they were stored at 0-4°C in Custodiol preservation solution for 240 min. Fresh-excised and cold-stored ischaemic hearts were used as controls. The viability of the different groups was assessed by comparing heart rate and left ventricular contractility in a Langendorff circuit, as well as perfusate levels of troponin-t and creatine kinase (CK), and myocardial levels of adenosine triphosphate (ATP) and reduced glutathione.
RESULTS: During ex vivo reperfusion, hearts in all groups resumed beating within minutes. The mean heart rate was highest in the 37°C group at 154.72 ± 33.01 beats × min(-1) (bpm), and declined in proportion to temperature to 39.72 ± 5.53 bpm at 20°C. Troponin-t levels were highest in the 37°C group (79.49 ± 20.79 µg/l), the values were significantly lower in all other reconditioned groups with a minimum of 12.472 ± 7.08 µg/l in the 20°C group (P < 0.0001). Tissue ATP levels ranged from 4.32 ± 1.71 µmol/g at 33°C to 4.59 ± 1.41 µmol/g at 30°C, all significantly higher than the mean ATP level of 1.41 ± 0.93 µmol/g in untreated ischaemic hearts (P < 0.0001). During Langendorff assessment, the mean heart rate and contractility of all groups were higher than those of cold-stored ischaemic hearts (P < 0.0001), yet not significantly different from those of fresh controls. The perfusate levels of troponin-t and CK, and myocardial levels of reduced-glutathione and ATP were not significantly different between groups.
CONCLUSION: Our results suggest that mild hypothermia during ex vivo reperfusion improves recovery of ischaemic hearts in a rodent DCD model.

PMID: 25740820 [PubMed – indexed for MEDLINE]

Evaluation of the organ care system in heart transplantation with an adverse donor/recipient profile. November 18, 2018
Icon for Elsevier Science Related Articles

Evaluation of the organ care system in heart transplantation with an adverse donor/recipient profile.

Ann Thorac Surg. 2014 Dec;98(6):2099-105; discussion 2105-6

Authors: García Sáez D, Zych B, Sabashnikov A, Bowles CT, De Robertis F, Mohite PN, Popov AF, Maunz O, Patil NP, Weymann A, Pitt T, McBrearty L, Pates B, Hards R, Amrani M, Bahrami T, Banner NR, Simon AR

Abstract
BACKGROUND: A severe shortage of available donor organs has created an impetus to use extended criteria organs for heart transplantation. Although such attempts increase donor organ availability, they may result in an adverse donor-recipient risk profile. The TransMedics Organ Care System (OCS) (TransMedics, Inc, Boston) allows preservation of the donor heart by perfusing the organ at 34°C in a beating state, potentially reducing the detrimental effect of cold storage and providing additional assessment options. We describe a single-center experience with the OCS in high-risk heart transplant procedures.
METHODS: Thirty hearts were preserved using the OCS between February 2013 and January 2014, 26 of which (86.7%) were transplanted. Procedures were classified as high risk based on (1) donor factors, ie, transport time more than 2.5 hours with estimated ischemic time longer than 4 hours, left ventricular ejection fraction (LVEF) less than 50%, left ventricular hypertrophy (LVH), donor cardiac arrest, alcohol/drug abuse, coronary artery disease or (2) recipient factors, ie, mechanical circulatory support or elevated pulmonary vascular resistance (PVR), or both.
RESULTS: Donor and recipient age was 37 ± 12 years and 43 ± 13 years, respectively. Allograft cold ischemia time was 85 ± 17 minutes and OCS perfusion time was 284 ± 90 minutes. The median intensive care unit stay was 6 days. One death (3.8%) was observed over the follow-up: 257 ± 116 (109-445 days). There was preserved allograft function in 92% of patients, with a mean LVEF of 64% ± 5%.
CONCLUSIONS: Use of the OCS is associated with markedly improved short-term outcomes and transplant activity by allowing use of organs previously not considered suitable for transplantation or selection of higher risk recipients, or both.

PMID: 25443013 [PubMed – indexed for MEDLINE]

Characterizing cardiac donation after circulatory death: implications for perfusion preservation. November 18, 2018
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Characterizing cardiac donation after circulatory death: implications for perfusion preservation.

Ann Thorac Surg. 2014 Dec;98(6):2107-13; discussion 2113-4

Authors: Brant SM, Cobert ML, West LM, Shelton JM, Jessen ME, Peltz M

Abstract
BACKGROUND: Donation after circulatory determination of death (DCDD) involves variable definitions of death among hospitals, and DCDD hearts are not generally considered for transplantation. The definition can affect ischemic times, and machine perfusion preservation appears promising for recovery of DCDD hearts. The purpose of the current study was to investigate the agonal phase of DCDD donors and evaluate retrograde perfusion preservation of DCDD donor hearts in a large animal model of cardiac transplantation.
METHODS: Ten canines were anesthetized and then disconnected from mechanical ventilation. Time to loss of pulse (systolic blood pressure <50 mm Hg), loss of pressure, and asystole or fibrillation were recorded. Five minutes after asystole, hearts were exposed and arrested with 1 L of University of Wisconsin Machine Perfusion Solution. Eight hearts were cold preserved for 4 hours by retrograde machine perfusion or static storage (n = 4/group), then reimplanted and reperfused for 6 hours. The preload recruitable stroke work was used to measure myocardial function.
RESULTS: The agonal phase was similar between groups. Loss of pulse and pressure were consistent between animals (7.9 ± 0.5 minutes [range, 5 to 11 minutes], 10.2 ± 0.4 minutes [range, 9 to 13 minutes], respectively). Electrical silence was variable at 26.9 ± 3.8 minutes (range, 11 to 43 minutes). All perfused hearts separated and remained off cardiopulmonary bypass. Three of four static hearts initially separated from cardiopulmonary bypass, but two returned by the end of the reperfusion period. The preload recruitable stroke work was significantly higher in perfused hearts.
CONCLUSIONS: Protocols for DCDD have implications on ischemic times of donor hearts. Machine perfusion preservation can recover DCDD hearts more consistently than static storage.

PMID: 25443014 [PubMed – indexed for MEDLINE]

A whole blood-based perfusate provides superior preservation of myocardial function during ex vivo heart perfusion. November 18, 2018
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A whole blood-based perfusate provides superior preservation of myocardial function during ex vivo heart perfusion.

J Heart Lung Transplant. 2015 Jan;34(1):113-21

Authors: White CW, Hasanally D, Mundt P, Li Y, Xiang B, Klein J, Müller A, Ambrose E, Ravandi A, Arora RC, Lee TW, Hryshko LV, Large S, Tian G, Freed DH

Abstract
BACKGROUND: Ex vivo heart perfusion (EVHP) provides the opportunity to resuscitate unused donor organs and facilitates assessments of myocardial function that are required to demonstrate organ viability before transplantation. We sought to evaluate the effect of different oxygen carriers on the preservation of myocardial function during EVHP.
METHODS: Twenty-seven pig hearts were perfused ex vivo in a normothermic beating state for 6 hours and transitioned into working mode for assessments after 1 (T1), 3 (T3), and 5 (T5) hours. Hearts were allocated to 4 groups according to the perfusate composition. Red blood cell concentrate (RBC, n = 6), whole blood (RBC+Plasma, n = 6), an acellular hemoglobin-based oxygen carrier (HBOC, n = 8), or HBOC plus plasma (HBOC+Plasma, n = 7) were added to STEEN Solution (XVIVO Perfusion, Goteborg, Sweden) to achieve a perfusate hemoglobin concentration of 40 g/liter.
RESULTS: The perfusate composition affected the preservation of systolic (T5 dP/dtmax: RBC+Plasma = 903 ± 99, RBC = 771 ± 77, HBOC+Plasma = 691 ± 82, HBOC = 563 ± 52 mm Hg/sec; p = 0.047) and diastolic (T5 dP/dtmin: RBC+Plasma = -574 ± 48, RBC = -492 ± 63, HBOC+Plasma = -326 ± 32, HBOC = -268 ± 22 mm Hg/sec; p < 0.001) function, and the development of myocardial edema (weight gain: RBC+Plasma = 6.6 ± 0.9, RBC = 6.6 ± 1.2, HBOC+Plasma = 9.8 ± 1.7, HBOC = 16.3 ± 1.9 g/hour; p < 0.001) during EVHP. RBC+Plasma hearts exhibited less histologic evidence of myocyte damage (injury score: RBC+Plasma = 0.0 ± 0.0, RBC = 0.8 ± 0.3, HBOC+Plasma = 2.6 ± 0.2, HBOC = 1.75 ± 0.4; p < 0.001) and less troponin-I release (troponin-I fold-change T1-T5: RBC+Plasma = 7.0 ± 1.7, RBC = 13.1 ± 1.6, HBOC+Plasma = 20.5 ± 1.1, HBOC = 16.7 ± 5.8; p < 0.001). Oxidative stress was minimized by the addition of plasma to RBC and HBOC hearts (oxidized phosphatidylcholine compound fold-change T1-T5: RBC+Plasma = 1.83 ± 0.20 vs RBC = 2.31 ± 0.20, p < 0.001; HBOC+Plasma = 1.23 ± 0.17 vs HBOC = 2.80 ± 0.28, p < 0.001).
CONCLUSIONS: A whole blood-based perfusate (RBC+Plasma) minimizes injury and provides superior preservation of myocardial function during EVHP. The beneficial effect of plasma on the preservation of myocardial function requires further investigation.

PMID: 25447577 [PubMed – indexed for MEDLINE]

Changing paradigms in organ preservation and resuscitation. November 18, 2018
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Changing paradigms in organ preservation and resuscitation.

Curr Opin Organ Transplant. 2015 Apr;20(2):152-8

Authors: Ali F, Dua A, Cronin DC

Abstract
PURPOSE OF REVIEW: Shortage of donor organs has increased consideration for use of historically excluded grafts. Ex-vivo machine perfusion is an emerging technology that holds the potential for organ resuscitation and reconditioning, potentially increasing the quality and number of organs available for transplantation. This article aims to review the recent advances in machine perfusion and organ preservation solutions.
RECENT FINDINGS: Flow and pressure-based machine perfusion has shown improved kidney graft function and survival, especially among expanded criteria donors. Pressure-based machine perfusion is demonstrating promising results in preservation and resuscitation of liver, pancreas, heart, and also lung grafts. August 2014 marked Food and Drug Administration approval of XPS XVIVO Perfusion System (XVIVO Perfusion Inc., Englewood, Colorado, USA), a device for preserving and resuscitating lung allografts initially considered unsuitable for transplantation. Although there is no consensus among physicians about the optimal preservation solution, adding antiapoptotic and cell protective agents to preservation solutions is an interesting research area that offers potential to improve preservation.
SUMMARY: Ex-vivo machine perfusion of solid organs is a promising method that provides the opportunity for resuscitation and reconditioning of suboptimal grafts, expanding the number and quality of donor organs.

PMID: 25719899 [PubMed – indexed for MEDLINE]

Low-flow hypothermic crystalloid perfusion is superior to cold storage during prolonged heart preservation. November 18, 2018
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Low-flow hypothermic crystalloid perfusion is superior to cold storage during prolonged heart preservation.

Transplant Proc. 2014 Dec;46(10):3309-13

Authors: Ou R, Lim YW, Choong JW, Esmore DS, Salamonsen RF, McLean C, Forbes J, Bailey M, Rosenfeldt FL

Abstract
BACKGROUND: Preservation of donor hearts for transplantation has traditionally been performed with the use of static cold storage. We have developed and tested a novel gravity-powered system of cold crystalloid perfusion for prolonged donor heart preservation.
METHODS: Greyhounds were anesthetized; their hearts were arrested with cold cardioplegic solution and excised. Hearts were allocated to 12 hours of perfusion preservation (n = 6) or cold storage in ice (n = 5). Non-preserved hearts (n = 5) served as a normal reference group. Perfusion hearts were perfused (20 mL/min, 8-12°C) with a novel oxygenated nutrient-containing preservation solution. After preservation, the recovery of the hearts was assessed in a blood-perfused working heart rig over 2 hours in terms of function, blood lactate level, myocardial adenosine triphosphate, and histology.
RESULTS: After 2 hours of reperfusion, in comparison with cold storage hearts, perfused heart function curves showed superior recovery of cardiac output (P = .001), power (P = .001), and efficiency (0.046 ± 0.01 vs 0.004 ± 0.003 joules/mL O2, P = .034). Myocardial adenosine triphosphate content (mmol/mg protein) was reduced significantly from the normal level of 26.5 (15.9, 55.8) to 5.08 (0.50, 10.4) (P = .049) in cold storage hearts but not in perfused hearts. Over a period of 2 hours, lactate levels in the blood perfusate were significantly lower in the perfusion group than in the cold storage group (P < .05).
CONCLUSIONS: Continuous hypothermic crystalloid perfusion provides myocardial preservation superior to cold storage for long-term heart preservation, with potential applicability to marginal and donation after circulatory death hearts.

PMID: 25498042 [PubMed – indexed for MEDLINE]

Normothermic ex vivo perfusion provides superior organ preservation and enables viability assessment of hearts from DCD donors. November 18, 2018
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Normothermic ex vivo perfusion provides superior organ preservation and enables viability assessment of hearts from DCD donors.

Am J Transplant. 2015 Feb;15(2):371-80

Authors: Iyer A, Gao L, Doyle A, Rao P, Cropper JR, Soto C, Dinale A, Kumarasinghe G, Jabbour A, Hicks M, Jansz PC, Feneley MP, Harvey RP, Graham RM, Dhital KK, MacDonald PS

Abstract
The shortage of donors in cardiac transplantation may be alleviated by the use of allografts from donation after circulatory death (DCD) donors. We have previously shown that hearts exposed to 30 min warm ischemic time and then flushed with Celsior supplemented with agents that activate ischemic postconditioning pathways, show complete recovery on a blood-perfused ex vivo working heart apparatus. In this study, these findings were assessed in a porcine orthotopic heart transplant model. DCD hearts were preserved with either normothermic ex vivo perfusion (NEVP) using a clinically approved device, or with standard cold storage (CS) for 4 h. Orthotopic transplantation into recipient animals was subsequently undertaken. Five of six hearts preserved with NEVP demonstrated favorable lactate profiles during NEVP and all five could be weaned off cardiopulmonary bypass posttransplant, compared with 0 of 3 hearts preserved with CS (p < 0.05, Fisher’s exact test). In conclusion, DCD hearts flushed with supplemented Celsior solution and preserved with NEVP display viability before and after transplantation. Viability studies of human DCD hearts using NEVP are warranted.

PMID: 25612491 [PubMed – indexed for MEDLINE]

Ex vivo heart perfusion after cardiocirculatory death; a porcine model. November 18, 2018
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Ex vivo heart perfusion after cardiocirculatory death; a porcine model.

J Surg Res. 2015 May 01;195(1):311-4

Authors: García Sáez D, Elbetanony A, Lezberg P, Hassanein A, Bowles CT, Popov AF, Zych B, Sabashnikov A, Mohite P, Simon AR

Abstract
BACKGROUND: Donation after cardiocirculatory death (DCD) has lead to an increase in organ availability. However, because of medical, logistic, and ethical issues, the use of hearts from DCD donors for transplantation is not generally considered to be feasible. In this study, we investigated the feasibility of ex vivo resuscitation and assessment of the porcine heart after circulatory death using the organ care system (OCS).
METHODS: Cardiocirculatory death was induced in five pigs by cessation of mechanical ventilation. No heparin was administered. The agonal time (AT) was calculated as the time between a reduction of blood pressure <50 mm Hg or a fall in saturation beneath 70% and the cessation of electrical activity. After a further 15 min of warm ischemia, hearts were procured and implanted into the OCS, mimicking the actual clinical scenario for other organs. Thus, procured grafts were assessed ex vivo over a period of 4 h.
RESULTS: Four hearts were successfully resuscitated on the system (AT 8, 15, 20, and 34 min) Three grafts had excellent visual contractility and lactate trends and were considered to be transplantable. One graft (AT 34 min) had an increased lactate and abnormal contractility being unsuitable for transplantation. One heart with 48-min AT could not be resuscitated.
CONCLUSIONS: Our data show that hearts from nonheparinized DCD porcine donors can be successfully resuscitated using the OCS in a scenario, which closely simulates clinical conditions.

PMID: 25617972 [PubMed – indexed for MEDLINE]

Extracorporeal heart perfusion before heart transplantation: the heart in a box. November 18, 2018
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Extracorporeal heart perfusion before heart transplantation: the heart in a box.

Curr Opin Organ Transplant. 2016 06;21(3):336-42

Authors: Macdonald PS, Chew HC, Connellan M, Dhital K

Abstract
PURPOSE OF REVIEW: Cold static storage is a time-tested and simple method of preserving hearts retrieved from optimal donors after brain death (DBD). The increasing gap between supply and demand for donor organs together with changing donor and recipient characteristics have led to renewed interest in the use of machine perfusion to increase both the quality and quantity of donor hearts for transplantation.
RECENT FINDINGS: Two major approaches to machine perfusion of donor hearts have been investigated – hypothermic (HMP) and normothermic machine perfusion (NMP). Recent preclinical studies with HMP confirm that it provides superior donor heart preservation to cold static storage. HMP systems have been developed for human heart preservation but have yet to be tested clinically. In contrast, NMP has undergone extensive clinical evaluation in human heart transplantation, including optimal and higher risk DBD donors. In addition, NMP has enabled distant procurement and successful transplantation of hearts retrieved from human donation after circulatory death donors.
SUMMARY: Initial clinical experience suggests that NMP of donor hearts retrieved from higher risk DBD and donation after circulatory death donors enables well tolerated ex-vivo reanimation, preservation, and assessment of these organs. In particular, this technology allows successful utilization of extended-criteria donor hearts that would otherwise be discarded.

PMID: 26967996 [PubMed – indexed for MEDLINE]

Safe orthotopic transplantation of hearts harvested 24 hours after brain death and preserved for 24 hours. November 18, 2018
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Safe orthotopic transplantation of hearts harvested 24 hours after brain death and preserved for 24 hours.

Scand Cardiovasc J. 2016 Jun;50(3):193-200

Authors: Steen S, Paskevicius A, Liao Q, Sjöberg T

Abstract
OBJECTIVES: The aim of this study was to demonstrate safe orthotopic transplantation of porcine donor hearts harvested 24 hours after brain death and preserved for 24 hours before transplantation.
DESIGN: Circulatory normalization of brain dead (decapitated) pigs was obtained using a new pharmacological regimen (n = 10). The donor hearts were perfused at 8 °C in cycles of 15 min perfusion followed by 60 min without perfusion. The perfusate consisted of an albumin-containing hyperoncotic cardioplegic nutrition solution with hormones and erythrocytes. Orthotopic transplantation was done in 10 recipient pigs after 24 hours’ preservation. Transplanted pigs were monitored for 24 hours, then an adrenaline stress test was done.
RESULTS: All transplanted pigs were stable throughout the 24-hour observation period with mean aortic pressure around 80 mmHg and normal urine production. Mean right and left atrial pressures were in the range of 3-6 and 5-10 mmHg, respectively. Blood gases at 24 hours did not differ from baseline values. The adrenaline test showed a dose dependent response, with aortic pressure increasing from 98/70 to 220/150 mmHg and heart rate from 110 to 185 beats/min.
CONCLUSION: Orthotopic transplantation of porcine hearts harvested 24 hours after brain death and preserved for 24 hours can be done safely.

PMID: 26882241 [PubMed – indexed for MEDLINE]

Assessment of donor heart viability during ex vivo heart perfusion. November 18, 2018
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Assessment of donor heart viability during ex vivo heart perfusion.

Can J Physiol Pharmacol. 2015 Oct;93(10):893-901

Authors: White CW, Ambrose E, Müller A, Li Y, Le H, Hiebert B, Arora R, Lee TW, Dixon I, Tian G, Nagendran J, Hryshko L, Freed D

Abstract
Ex vivo heart perfusion (EVHP) may facilitate resuscitation of discarded donor hearts and expand the donor pool; however, a reliable means of demonstrating organ viability prior to transplantation is required. Therefore, we sought to identify metabolic and functional parameters that predict myocardial performance during EVHP. To evaluate the parameters over a broad spectrum of organ function, we obtained hearts from 9 normal pigs and 37 donation after circulatory death pigs and perfused them ex vivo. Functional parameters obtained from a left ventricular conductance catheter, oxygen consumption, coronary vascular resistance, and lactate concentration were measured, and linear regression analyses were performed to identify which parameters best correlated with myocardial performance (cardiac index: mL·min(-1)·g(-1)). Functional parameters exhibited excellent correlation with myocardial performance and demonstrated high sensitivity and specificity for identifying hearts at risk of poor post-transplant function (ejection fraction: R(2) = 0.80, sensitivity = 1.00, specificity = 0.85; stroke work: R(2) = 0.76, sensitivity = 1.00, specificity = 0.77; minimum dP/dt: R(2) = 0.74, sensitivity = 1.00, specificity = 0.54; tau: R(2) = 0.51, sensitivity = 1.00, specificity = 0.92), whereas metabolic parameters were limited in their ability to predict myocardial performance (oxygen consumption: R(2) = 0.28; coronary vascular resistance: R(2) = 0.20; lactate concentration: R(2) = 0.02). We concluded that evaluation of functional parameters provides the best assessment of myocardial performance during EVHP, which highlights the need for an EVHP device capable of assessing the donor heart in a physiologic working mode.

PMID: 26317524 [PubMed – indexed for MEDLINE]

Twelve-Hour Hypothermic Machine Perfusion for Donor Heart Preservation Leads to Improved Ultrastructural Characteristics Compared to Conventional Cold Storage. November 18, 2018
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Twelve-Hour Hypothermic Machine Perfusion for Donor Heart Preservation Leads to Improved Ultrastructural Characteristics Compared to Conventional Cold Storage.

Ann Transplant. 2015 Aug 11;20:461-8

Authors: Michel SG, La Muraglia GM, Madariaga ML, Titus JS, Selig MK, Farkash EA, Allan JS, Anderson LM, Madsen JC

Abstract
BACKGROUND Hypothermic machine perfusion of donor hearts has the theoretical advantage of continuous aerobic metabolism and washes out toxic metabolic byproducts. Here, we studied the effect of hypothermic machine perfusion on cardiac myocyte integrity when hearts are preserved for longer ischemic times (12 hours). MATERIAL AND METHODS Pig hearts were harvested and stored in Celsior® solution for 12 hours using either conventional cold storage on ice (12 h CS, n=3) or pulsatile perfusion with the Paragonix Sherpa Perfusion™ Cardiac Transport System at different flow rates (12 h PP, n=3 or 12 h PP low flow, n=2). After cold preservation, hearts were reperfused using an LV isovolumic Langendorff system. Controls (n=3) were reperfused immediately after organ harvest. Biopsies were taken from the apex of the left ventricle before storage, after storage and after reperfusion to measure ATP and endothelin-1 content in the tissue. TUNEL staining for signs of apoptosis and electron microscopy of the donor hearts were performed. RESULTS 12 h PP hearts showed significantly more weight gain than 12 h CS and controls after preservation. Pulsatile perfused hearts showed less ATP depletion, lower endothelin-1 levels and less apoptosis after preservation compared to CS. Electron microscopy showed damaged muscle fibers, endothelial cell rupture, and injury of mitochondria in the 12 h CS group, while machine perfusion could preserve the cell structures. CONCLUSIONS Hypothermic machine perfusion of donor hearts can preserve the cell structures better than conventional cold storage in prolonged ischemic times. Hypothermic pulsatile perfusion may therefore enable longer preservation times of donor hearts. Whether this method is able to avoid primary graft failure after orthotopic heart transplantation remains to be evaluated in further studies.

PMID: 26259549 [PubMed – indexed for MEDLINE]

Cold Crystalloid Perfusion Provides Cardiac Preservation Superior to Cold Storage for Donation After Circulatory Death. November 18, 2018
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Cold Crystalloid Perfusion Provides Cardiac Preservation Superior to Cold Storage for Donation After Circulatory Death.

Transplantation. 2016 Mar;100(3):546-53

Authors: Choong JW, Ou R, Lim YW, Rosenfeldt FL

Abstract
BACKGROUND: We previously showed that donation after circulatory death (DCD) canine hearts can be resuscitated if perfused with warm blood. However, clinical application of this technique is complex and difficult. We have developed a simplified system of cold crystalloid perfusion and compared it with standard cold storage for DCD heart preservation.
METHODS: Anesthetized greyhounds underwent 30 minutes DCD by withdrawal of ventilation followed by assignment to either 4 hours of perfusion (n = 6) or cold storage (n = 7). Nonpreserved hearts (n = 5) served as a normal reference group. Perfusion hearts were reperfused with a protective solution then perfused for 4 hours with a novel oxygenated, nutrient-containing solution at 20 mL/min at 4°C to 10°C. Cold storage hearts were flushed with St Thomas’ cardioplegic solution and stored in ice. After preservation, the recovery of the hearts was assessed on a blood-perfused working heart rig.
RESULTS: During preservation, perfusion hearts consumed oxygen (0.09 ± 0.01 mL/100 g per minute) and showed decreasing lactate production in the perfusate (initial: 0.031 ± 0.004 vs final: 0.007 ± 0.002 mmol/min; P = 0.001). After preservation, compared to cold storage hearts, perfusion hearts had higher cardiac output (P = 0.004), LV dP/dt max (P = 0.003) and myocardial oxygen efficiency (P = 0.01), with lower blood perfusate lactate (P = 0.007). Hemodynamic values of perfused hearts reached 60% or more those in the normal reference group.
CONCLUSIONS: Continuous cold crystalloid perfusion in a canine model of DCD: (1) facilitates aerobic metabolism and resuscitates the DCD heart, (2) provides functional and metabolic recovery superior to cold storage, (3) shows promise for improved clinical preservation of DCD and marginal donor hearts.

PMID: 26569064 [PubMed – indexed for MEDLINE]

Hypothermic continuous machine perfusion enables preservation of energy charge and functional recovery of heart grafts in an ex vivo model of donation following circulatory death. November 18, 2018
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Hypothermic continuous machine perfusion enables preservation of energy charge and functional recovery of heart grafts in an ex vivo model of donation following circulatory death.

Eur J Cardiothorac Surg. 2016 May;49(5):1348-53

Authors: Van Caenegem O, Beauloye C, Bertrand L, Horman S, Lepropre S, Sparavier G, Vercruysse J, Bethuyne N, Poncelet AJ, Gianello P, Demuylder P, Legrand E, Beaurin G, Bontemps F, Jacquet LM, Vanoverschelde JL

Abstract
OBJECTIVES: Cardiac transplantation using hearts from donors after circulatory death (DCD) is critically limited by the unavoidable warm ischaemia and its related unpredictable graft function. Inasmuch as hypothermic machine perfusion (MP) has been shown to improve heart preservation, we hypothesized that MP could enable the use of DCD hearts for transplantation.
METHODS: We recovered 16 pig hearts following anoxia-induced cardiac arrest and cardioplegia. Grafts were randomly assigned to two different groups of 4-h preservation using either static cold storage (CS) or MP (Modified LifePort© System, Organ Recovery Systems©, Itasca, Il). After preservation, the grafts were reperfused ex vivo using the Langendorff method for 60 min. Energetic charge was quantified at baseline, post-preservation and post-reperfusion by measuring lactate and high-energy phosphate levels. Left ventricular contractility parameters were assessed both in vivo prior to ischaemia and ex vivo during reperfusion.
RESULTS: Following preservation, the hearts that were preserved using CS exhibited higher lactate levels (57.1 ± 23.7 vs 21.4 ± 12.2 µmol/g; P < 0.001), increased adenosine monophosphate/adenosine triphosphate ratio (0.53 ± 0.25 vs 0.11 ± 0.11; P < 0.001) and lower phosphocreatine/creatine ratio (9.7 ± 5.3 vs 25.2 ± 11; P < 0.001) in comparison with the MP hearts. Coronary flow was similar in both groups during reperfusion (107 ± 9 vs 125 ± 9 ml/100 g/min heart; P = ns). Contractility decreased in the CS group, yet remained well preserved in the MP group.
CONCLUSION: MP preservation of DCD hearts results in improved preservation of the energy and improved functional recovery of heart grafts compared with CS.

PMID: 26604296 [PubMed – indexed for MEDLINE]

Design and Evolution of the Asporto Heart Preservation Device. November 18, 2018
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Design and Evolution of the Asporto Heart Preservation Device.

J Extra Corpor Technol. 2015 Jun;47(2):119-24

Authors: Rivard AL

Abstract
The Asporto Heart Preservation Device is a system providing perfusion of cardioplegia to the donor heart using a computer-controlled peristaltic pump in a thermoelectrically cooled and insulated container. In 1998, a user interface was developed at the University of Minnesota consisting of a touch screen and battery-backed microcontroller. Power was supplied by a 120 VAC to 12 VDC converter. An upgrade to the insulated cooler and microcontroller occurred in 2002, which was followed by proof of concept experimental pre-clinical transplants and tests demonstrating the efficacy of the device with isolated donor hearts. During the period between 2002 and 2006, a variety of donor organ containers were developed, modified, and tested to provide an optimal sterile environment and fluid path. Parallel development paths encompass formalized design specifications for final prototypes of the touch screen/microcontroller, organ container, and thermoelectric cooler.

PMID: 26405361 [PubMed – indexed for MEDLINE]

Donor Organ Turn-Downs and Outcomes Following Listing for Pediatric Heart Transplant September 28, 2018

Pediatric heart transplant waitlist mortality remains significant but allograft offer refusals are common and allografts continue to be discarded.

PREDICTED HEART MASS IS THE OPTIMAL METRIC FOR SIZE MATCH IN HEART TRANSPLANTATION September 26, 2018

Traditionally, donor-recipient size match is assessed by body weight. We assessed the ability of 5 size match metrics – predicted heart mass (PHM), weight, height, body mass index (BMI) and body surface area (BSA) – to predict 1-year mortality after heart transplant and to assess the effect on size match on donor heart turn-down for size.

Obstacles to Improving Outcomes of Heart Transplantation for Adults with Congenital Heart Disease September 14, 2018

Adults with congenital heart disease (ACHD) represent a growing, albeit still small, proportion of heart transplant (HT) recipients (1, 2). These patients frequently present with complex anatomy and physiology, and atypical manifestations of cardiac failure. Despite being younger than other HT candidates, they have higher risk for adverse outcomes early after HT. This relates to prior thoracic operations, longer allograft ischemic time, a high prevalence of sensitization, less frequent use of pre-transplant mechanical circulatory support (1), and underappreciated end-organ dysfunction.

Clinical Implications of the Total Artificial Heart: Adversity and Progress August 7, 2018

The history of the SynCardia Total Artificial Heart – temporary (TAH-t; SynCardia Systems, LLC, Tuscon, AZ) is a fascinating medical tale of success, failure and perseverance that has highlighted the lives of many physicians, scientists and patients while episodically consuming the attention of the public. Although, perhaps not as dramatic as its first implantation in a human in 1982, a major and significant milestone in the history of this device was the Food and Drug Administration (FDA) approval of the SynCardia TAH-t in October of 2004 for bridge to transplant indication in the United States, culminating decades of scientific investigation and clinical study and making this device available for commercial use.

Worldwide trends in heart and lung transplantation: Guarding the most precious gift ever. July 19, 2018
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Worldwide trends in heart and lung transplantation: Guarding the most precious gift ever.

Best Pract Res Clin Anaesthesiol. 2017 Jun;31(2):141-152

Authors: von Dossow V, Costa J, D’Ovidio F, Marczin N

Abstract
Transplantation is sadly a therapy to die for. The survival of a recipient with end-stage heart or lung disease requires the demise of a human being through brain death or cessation of circulation, with the noblest final act of offering one’s organs to another. However, transplantation is constrained by severe hemodynamic, regulatory, inflammatory, and metabolic stresses in the donor, rendering the majority of offered organs unsuitable for transplantation. Coupled with our inability to acquire exact molecular and cellular information and missed opportunities for effectively modulating deteriorations of donors and allografts, anesthesia and critical care contributes to ongoing organ shortages. Progress is made with improving waiting lists by bridging patients for transplantation using mechanical support. However, this represents more complex recipients, higher risk transplant operations, and increased resource utilization. The advent of ex vivo perfusion allows implementing novel diagnostic and therapeutic strategies with real potential of reconditioning less ideal organs. This review advocates a paradigm change in critical care management of the potential donor for improving retrieval practices and for more intellectual involvement of our specialties in organ preservation, ex vivo evaluation and reconditioning, and the need for great advancement in our efficiency in converting unacceptable allografts to suitable donor organs.

PMID: 29110788 [PubMed – indexed for MEDLINE]

Center Volume and Post-Transplant Survival Among Adults with Congenital Heart Disease July 15, 2018

Eighty five percent of congenital heart disease patients currently survive to adulthood due primarily to advancements in surgical treatments1. For these survivors with Adult Congenital Heart Disease (ACHD), heart failure (HF) remains the leading cause of death2. Thus, the number of ACHD patients requiring heart transplantation (HT) continues to grow, and with this growth has come improvements in outcomes. In 2009, Lamour et al. demonstrated a 1-year survival of 83% for non-Fontan congenital HT and 71% for patients with Fontan palliation3.

MICRORNAS SIGNATURES IN CARDIAC BIOPSIES AND DETECTION OF ALLOGRAFT REJECTION July 2, 2018

Identification of heart transplant rejection currently rely on immunohistologic and immunohistochemistry. We aimed to identify specific sets of microRNAs (miRNAs) to characterize acute cellular (ACR), antibody-mediated (pAMR) and mixed (MR) rejections in monitoring formalinfixed paraffin-embedded (FFPE) endomyocardial biopsies (EMBs) in heart transplant (HTx) patients.

Upcoming heart allocation policy change June 21, 2018

If you are a patient on the national waiting list for a heart, your urgency for a transplant is currently based on three statuses:

  • 1A (most urgent)
  • 1B (somewhat urgent)
  • 2 (least urgent)

As we learn more about heart disease and successful treatment of it, the transplant community determined we needed more specific criteria that reflects a heart patient’s current health and care they are getting. To accommodate these needs, we are making changes to heart policy and the first phase of the new heart allocation policy will take effect on September 18.

Heart candidates can find specific information here about how this change will affect you. You can also download a print version from the website.

Temporary circulatory support devices as a bridge to transplant: Boon or bane? June 12, 2018

The allocation of donor hearts evolves in response to the changing landscape of advanced heart failure therapies and expanded understanding of donor/recipient matching. The novel, heart allocation algorithm is a natural response to the success of mechanical circulatory support (MCS) and further aligns severity of illness with urgency. In the novel, 6-status system, candidates supported with veno-arterial, extracorporeal membrane oxygenation devices (ECMO) and biventricular, extracorporeal ventricular assist devices (VAD) receive Status 1 urgency, while Status 2 urgency comprises candidates with univentricular extracorporeal VADs, percutaneous, endovascular mechanical circulatory support (e.g.

Donor heart selection and outcomes: An analysis of over 2,000 cases April 28, 2018

Decision-making when offered a donor heart for transplantation is complex, and supportive data describing outcomes according to acceptance or non-acceptance choices are sparse. Our aim was to analyze donor heart acceptance decisions and associated outcomes at a single center, and after subsequent acceptance elsewhere.

New booklet advises parents of pediatric transplant patients April 24, 2018

A new resource booklet, “What Every Parent Needs to Know,” is available for parents and caregivers of children and adolescents who need or receive an organ transplant. The OPTN/UNOS Patient Affairs Committee spearheaded the booklet’s development in collaboration with a number of transplant professionals and parents of organ transplant recipients*.

The booklet explains the transplant process from a parent’s viewpoint. It addresses issues before and during a transplant such as financial concerns and explaining deceased donation to a child, as well as guidance on helping children manage life after a transplant. It addresses a number of concepts and terms relating to transplantation and provides references to other helpful resources.

* The Patient Affairs Committee also wishes to thank the following organizations for reviewing the booklet:

  • American Liver Foundation
  • American Society of Transplantation
  • Anne & Robert H. Lurie Children’s Hospital of Chicago
  • Children’s Cardiomyopathy Foundation
  • Children’s Organ Transplant Association
  • International Pediatric Transplant Association
  • National Kidney Foundation
  • Pediatric Heart Transplant Study
OPTN/UNOS Board members named March 8, 2018

Richmond, Va. — Members of the national organ donation and transplantation community have elected 25 members to the OPTN/UNOS board of directors, including a new president, vice-president/president-elect, vice president for patient and donor affairs and secretary. United Network for Organ Sharing (UNOS) serves as the Organ Procurement and Transplantation Network (OPTN) under federal contract.

All board members are volunteers and serve terms ranging from one to three years, depending on the office to which they are elected. Their terms of service begin on July 1, 2018.

Sue Dunn, RN, B.S.N., M.B.A., currently the Vice President/President-Elect, will assume the presidency. She is president and chief executive officer of Donor Alliance in Denver.

Maryl Johnson, M.D., will become the Vice President/President-Elect. She is professor of medicine, heart failure and heart transplantation at the University of Wisconsin Hospitals and Clinics.

Deanna Santana, B.S., will become the Vice President for Patient and Donor Affairs. She is senior public education coordinator at Sierra Donor Services in Sacramento, Calif. She is also a donor mother and a living donor.

Theresa Daly, M.S., RN, B.S.N., FNP, will become the Secretary. She is director of transplant clinical operations at New York Presbyterian/Columbia Medical Center.

Other newly elected members are as follows:

Immediate Past President – Yolanda Becker, M.D., University of Chicago Medicine

Region 3 Councillor – Christopher Anderson, M.D., University of Mississippi Medical Center

Region 4 Councillor – Steven Potter, M.D., FACS, East Texas Medical Center

Region 5 Councillor – Kunam Reddy, M.D., Mayo Clinic, Phoenix

Region 6 Councillor – Susan Orloff, M.D., FACS, AASLD, Oregon Health & Science University

Region 9 Councillor – Rob Kochik, Finger Lakes Donor Recovery Network

At Large Abdominal Surgery Representative –, Rene Romero, M.D., Children’s Healthcare of Atlanta

At Large Hepatology Representative – Simon Horslen, M.B., Ch.B., Seattle Children’s Hospital

At Large Nephrology Representatives:
Eileen Brewer, M.D., Texas Children’s Hospital
Jerry McCauley, M.D., M.P.H., FACP, Thomas Jefferson University Hospital

At Large Pulmonology Representative – Marc Schecter, M.D., Children’s Hospital Medical Center, Cincinnati

At Large Transplant Administrator Representative – Timothy Stevens, RN, B.S.N. CCTC, Sacred Heart Medical Center

OPO Representative – Diane Brockmeier, RN, B.S.N., M.H.A., Mid-America Transplant Services

Histocompatibility Representative – Walter Herczyk, MT, CHS, Gift of Life Michigan Histocompatibility Laboratory

Transplant Coordinator Representative – Mary Francois, RN, M.S., CCTC, NATCO

Medical/Scientific Organization Representatives:
Sharon Bartosh, M.D., University of Wisconsin Hospital and Clinics
Charles Miller, M.D., Cleveland Clinic Foundation

Patient and Donor Affairs Representatives:
Randee Bloom, Ph.D., M.B.A., RN
Rosemary Berkery, J.D.
Laura DePiero, RN, B.S.N.
Joseph Hillenburg

Public comment sought January 22, 2018

The Organ Procurement and Transplantation Network (OPTN) offers policy proposals for public comment from January 22 through March 23, 2018.

Comments and replies will be published on the OPTN public comment page, to promote transparency and trust in the national transplant system. Visitors can also share comments on social media, if they wish.

Feedback for selected proposals will be sought via a response form. This is part of a trial to study potential enhancements to the public comment process. For the proposals using the response form, the comments related to the proposal will be displayed on the public comment page in the same manner as the blog-style responses to all other proposals.

One of the proposals is a draft of an updated OPTN/UNOS strategic plan. The plan, to be finalized by the OPTN/UNOS Board of Directors after public input, will serve as a roadmap to help prioritize the OPTN’s work through 2021 and provide metrics to assess progress toward key goals.

We encourage patients, transplant candidates and recipients, living donors, donor families and transplant professionals to learn more about the proposals below and provide valuable feedback to help shape U.S. organ transplant policy:

  • Aligning VCA program membership requirements with other transplant programs
  • Modifications to the distribution of deceased donor lungs
  • Clarifying informed consent policies for transmissible disease risk
  • Concept paper on expedited organ placement
  • Reducing reporting burdens and clarify policies on extra vessels
  • Guidance on optimizing VCA recovery from deceased donors
  • Changes to waiting time criteria for kidney pancreas candidates
  • Modifying the lung Transplant Recipient Form to improve post-transplant lung function data
  • Revising OPTN Bylaws Appendix L
  • White paper on manipulating waitlist priority
  • Guidance for ABO subtyping of Blood Type A and AB organ donors
  • Concept paper on improving the OPTN/UNOS committee structure
  • Guidance on deceased donor requested information
  • OPTN/UNOS strategic plan
  • Review board guidance on heart candidates with exceptions for HCM and RCM
Deceased organ donors in United States exceeded 10,000 for first time in 2017 January 9, 2018

During 2017, the number of deceased organ donors in the United States topped 10,000 for the first time, according to preliminary data from United Network for Organ Sharing (UNOS), which serves as the national Organ Procurement and Transplantation Network (OPTN) under federal contract. For the year, organs were recovered from 10,281 donors, representing a 3.1 percent increase over 2016 and an increase of 27 percent since 2007.

A total of 34,768 organ transplants were performed in 2017 using organs from both deceased and living donors, according to preliminary data. This total is a 3.4 percent increase over 2016 and marks the fifth consecutive record-setting year for transplants in the United States. Record number of donor organs were recovered and transplants occurred for each of the four most common organs transplanted – kidney, liver, heart and lung.

“We are grateful that more lives are being saved, year after year, thanks to the boundless generosity of organ donors,” said Yolanda Becker, M.D., president of the OPTN/UNOS Board of Directors. “We remain committed to increasing the number of transplants still further to help the many thousands of people in need of a transplant to sustain them and vastly improve their quality of life.”

Approximately 82 percent (28,587) of the transplants performed in 2017 involved organs from deceased donors. Living donor transplants accounted for the remaining 18 percent (6,181). In the 30-year span from 1988 (the first full year national transplant data were collected) through 2017, a total of 721,742 transplants have been performed nationwide.

While the number of potential organ donors varies among different areas of the country due to differences in population size and medical characteristics, increases were noted in many areas. Of the 58 organ procurement organizations (OPOs) coordinating deceased organ donation nationwide, 35 (60 percent) experienced an increase in donors from 2016 to 2017, including at least one OPO in each of UNOS’ 11 regions.

“Donation and transplantation continues to increase across the country,” said Brian Shepard, Chief Executive Officer of UNOS. “We are working with donation and transplantation professionals nationwide to help identify additional transplant opportunities and enhance the efficiency of the organ acceptance process.”

Broadening of clinical criteria for potential donors accounts for some of the ongoing increase in deceased organ donation and transplantation. In 2017, as compared to 2016, a higher proportion of donors had medical characteristics such as donation after circulatory death as opposed to brain death, drug intoxication as a mechanism of death, age of 50 or older, and/or being identified as having increased risk for blood-borne disease.

“As we increase our understanding of medical criteria that contribute to successful transplantation, donation and transplantation professionals have been able to use organs from a wider set of potential donors,” said David Klassen, M.D., UNOS Chief Medical Officer. “In doing so, we continue to carefully balance the opportunity for transplantation with a commitment to maintaining patient safety.”

United Network for Organ Sharing (UNOS) serves as the national Organ Procurement and Transplantation Network (OPTN) under contract with the Department of Health and Human Services, Health Resources and Services Administration. The OPTN brings together medical professionals, transplant recipients and donor families to develop national organ transplantation policy.

Board of Directors releases University Hospitals of Cleveland from probation October 3, 2017

At a meeting by teleconference October 3, 2017, the OPTN/UNOS Board of Directors restored full member privileges for University Hospitals of Cleveland, a transplant center in Cleveland, Ohio.

The Board had placed the hospital on probation in June 2016, after peer review of low transplant volume and early-term recipient deaths at its heart transplant program revealed concerns with the program’s quality management protocols. The hospital has since instituted actions that successfully address the previous concerns.

United Network for Organ Sharing (UNOS) serves as the national Organ Procurement and Transplantation Network (OPTN) under contract with the Department of Health and Human Services, Health Resources and Services Administration, Division of Transplantation. The OPTN brings together medical professionals, transplant recipients and donor families to develop national organ transplantation policy.