Name: Innovative Strategies for Organ Preservation in Heart Transplantation: Uniform Cooling Preservation and Ex-situ Normothermic Perfusion (Video) | JoVE Journal
Uploaded: 2025-11-28T13:00:00.000+00:00
Duration: 8 min 15 s
Description: Learn innovative heart preservation techniques including uniform cooling and ex-situ normothermic perfusion for cardiac transplantation. These methods reduce temperature variation and expand the donor pool to improve transplant outcomes.

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5 minutes

The translational program of heart transplantation and ex-situ organ perfusion at Marie Lannelongue Hospital is supported by research grants from the Fondation C&#339;ur et Recherche (Paris, France) and from the Association Chirurgicale pour le D&#233;veloppement et l&#39;Am&#233;lioration des Techniques de D&#233;pistage et de Traitement des Maladies Cardiovasculaire (ADETEC, Suresnes, France).

All animals included in this video protocol (using porcine hearts) received humane care in accordance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research, as well as the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 86-23, revised 1996). All procedures were conducted following approval for the use of animals in scientific research, granted by the French Ministry of Research (reference APAFiS#23716-2020012112432923v1). We obtained informed consent from the patients mentioned in this study to use and publish their data.
1. Uniform cooling preservation
<ol>
	<li>Retrieve the sterile nested canisters (the outer one protects the inner one) and place the inner one in a cup filled with ice. A &#34;cold atmosphere&#34; is therefore created around the inner canister.</li>
	<li>Fill the inner canister with 3 L of cold preservation solution (the same as that used for cardioplegic arrest of the donor heart), after validation of the suitability of the graft for transplant (visual inspection), and just before retrieval.</li>
	<li>Explant the donor heart conventionally with the longest possible ascending aorta to place the UCP-specific connector canula high enough to preserve sufficient length for the aortic anastomosis.</li>
	<li>Choose the appropriate size for the UCP aortic connector corresponding to the inner diameter of the ascending aorta.</li>
	<li>Secure the aortic canula into the aortic lumen with an external surgical loop.</li>
	<li>Connect the aortic canula to the inner canister cover to suspend the donor heart in the preservation solution.</li>
	<li>Deair the inner canister by slowly flushing the preservation solution through a dedicated port (fluid will exit from a second port located on the cover). Fill the canister with solution up to the top, then close it with its dedicated cap. Ensure the donor heart is completely submerged in the preservation solution.</li>
	<li>Place the inner canister inside the outer canister and lock the outer canister with its dedicated cover.</li>
	<li>Place the outer canister in the shipper and start temperature monitoring. Preservation temperature is visible on the anterior screen of the shipper and on the mobile phone application. 
	NOTE: No temperature adjustment is possible during organ transportation using UCP.</li>
	<li>Upon arrival of the procurement team at the recipient center, remove the donor heart from the inner canister (respecting sterile conditioning). Open the inner canister and gently disconnect the UCP aortic connector from the cover. Remove the connector from the ascending aorta.</li>
</ol>
2. Heart retrieval
<ol>
	<li>Perform a median sternotomy.</li>
	<li>Separate the ascending aorta from the pulmonary artery. Control the superior and inferior vena cava with a surgical loop.</li>
	<li>Inject heparin (300 IU/kg, IV). Wait 3 min after heparin administration, then canulate the ascending aorta above the origin of the right coronary artery for cardioplegia injection. 
	NOTE: Purge and connect the cardioplegia line to the aortic canula before blood collection. Blood collection may result in significant hemodynamic collapse with low pressure in the ascending aorta, making its canulation challenging. Another reason to secure the cardioplegia line to the aortic canula is to be ready for flushing after aortic cross-clamping as soon as blood collection is completed.</li>
	<li>Canulate the right atrium with a 32-French double-staged canula.</li>
	<li>Connect a sterile, heparinized bag (10,000 IU) to the right atrium cannula and collect 1,200 to 1,500 mL of blood. Allow 90-120 s for this process.</li>
	<li>Prime the circuit of the heart perfusion module with the donor blood collected after leukocyte filtering using a dedicated filter. Add 500 mL of saline priming solution containing 10% albumin, insulin, steroids, and antibiotics.</li>
	<li>Clamp the distal part of the ascending aorta and flush cold crystalloid cardioplegia solution to induce diastolic cardiac arrest.</li>
	<li>Explant the donor heart with the longest possible ascending aorta to place the aortic canula high enough to avoid coronary artery obstruction.</li>
	<li>Close the left atrial appendage if it was opened (in case of simultaneous lung procurement). Look for a patent foramen ovale and close it if present (one or two single stitches of 4.0 monofilament).</li>
</ol>
3. Heart instrumentation
<ol>
	<li>Place the heart in a sterile cup with a 4 &#176;C saline solution.</li>
	<li>Place four pledgetted sutures of 4.0 monofilament on the cardinal points of the distal ascending aorta.</li>
	<li>Choose the appropriate aortic cannula from the four available sizes to match the donor aorta diameter. Do not oversize the canula.</li>
	<li>Secure the aortic canula with an external cable tie to prevent accidental detachment of the heart from the connector during transport.</li>
	<li>Secure the malleable pulmonary cannula with a 4.0 monofilament running suture around the pulmonary trunk.</li>
	<li>Create a purse-string suture with 4-0 monofilament on the left atrium to secure the left ventricular vent cannula. Insert a canula vent into the left ventricle through the left atrium for deairing during ESHP.</li>
	<li>Close the superior vena cava with a 4.0 monofilament running suture.</li>
</ol>
4. Heart reperfusion on ESHP
<ol>
	<li>Reduce the pump flow to 1,000 mL/min and remove the shunt between the aortic and venous lines before positioning the heart.</li>
	<li>Place the heart upside down with the posterior ventricular walls facing the operator.</li>
	<li>De-air the ascending aorta and connect the aortic canula to the aortic line. 
	NOTE: Blood flow is delivered into the aorta in a retrograde manner, enabling coronary artery perfusion.</li>
	<li>Perform a gentle cardiac massage until the heart is warmed up.</li>
	<li>Deliver a 30 J shock in case of ventricular fibrillation to obtain a sinus rhythm.</li>
	<li>Place an epicardial pacing lead on the posterior wall of the right ventricle. Connect this lead to an external pacemaker and pace the heart at 80 beats/min.</li>
	<li>Slowly increase the pump flow to reach an aortic pressure of 65 mmHg.</li>
	<li>Close the inferior vena cava with a 4.0 monofilament running suture. 
	NOTE: At this point, all the deoxygenated blood flowing from the coronary sinus goes into the right atrium and is ejected through the pulmonary artery since the right ventricle is beating.</li>
	<li>De-air and connect the pulmonary cannula to the venous line. Place a flow probe on the venous line for continuous monitoring of the coronary blood flow. 
	NOTE: Warm venous blood enters the reservoir and is then pumped by a centrifugal pump through the gas exchanger. Warm oxygenated blood then goes to the aortic line. Once connected to the perfusion module, the isolated heart thus receives a warm (34 &#176;C), oxygenated, and nutrient-enriched perfusion.</li>
</ol>
5. Hemodynamic and metabolic monitoring during ESHP
<ol>
	<li>Maintain the mean aortic pressure between 70 and 85 mmHg and mean coronary flow between 650 and 850 mL/min. 
	NOTE: Coronary flow can be reduced by decreasing pump flow. Infusing a maintenance solution containing adenosine prevents coronary vasoconstriction and thus increases coronary flow. Increasing pump flow both leads to higher coronary flow and higher mean aortic pressure.</li>
	<li>Perform metabolic monitoring during ESHP by repeatedly measuring arterial and venous lactate concentrations every 30 min (or every 15 min after adjusting the maintenance solution flow rate or changing the pump flow) using an automated transportable analyzer.</li>
	<li>Optimize perfusion parameters and correct biochemical disorders (glycemia, Ca2+, K+, PO2, PCO2, pH) in response to an adverse lactate trend.</li>
	<li>Disqualify the donor heart from transplantation in case of persistent arterial lactate increase despite all corrective measures.</li>
</ol>
6. Termination of ESHP
<ol>
	<li>Connect the ESHP heart perfusion module to a water heater cooler via specific ports on the oxygenator membrane. Cool at 2 &#176;C intervals.</li>
	<li>Stop pacing the heart and disconnect the venous line when the heart rhythm drops below 50 bpm.</li>
	<li>At 16 &#176;C, stop the donor heart with the same crystalloid cardioplegia solution as the one used for initial cardiac arrest.</li>
	<li>Decannulate the heart from the ESHP perfusion module. Place the heart in a bowl of cold saline solution until implantation. 
	NOTE: ESHP using the OCS technology is not a platform for organ rehabilitation or repair. A poor-quality graft before organ procurement will remain an unsuitable heart for transplantation, even after several hours of ESHP. We would not recommend initiating an ESHP program using grafts from extended-criteria donors at the outset, as this may lead to unfavorable outcomes -- not due to the ESHP technology itself but because of the intrinsically poor quality of the grafts.</li>
</ol>

<ol><li>Radakovic, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((First+clinical+experience+with+the+novel+cold+storage+SherpaPak+system+for+donor+heart+transportation%5BTitle%5D)+AND+%22J+Thorac+Dis%22%5BJournal%5D)">First clinical experience with the novel cold storage SherpaPak system for donor heart transportation.</a> J Thorac Dis. 12 (12), 7227-7235 (2020).</li>
<li>Shudo, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((A+paradigm+shift+in+heart+preservation%3A+improved+post-transplant+outcomes+in+recipients+of+donor+hearts+preserved+with+the+SherpaPak+system%5BTitle%5D)+AND+%22ASAIO+J%22%5BJournal%5D)">A paradigm shift in heart preservation: improved post-transplant outcomes in recipients of donor hearts preserved with the SherpaPak system.</a> ASAIO J. 69 (11), 993-1000 (2023).</li>
<li>Moayedifar, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Recipient+outcomes+with+extended+criteria+donors+using+advanced+heart+preservation%3A+an+analysis+of+the+GUARDIAN-Heart+registry%5BTitle%5D)+AND+%22J+Heart+Lung+Transplant%22%5BJournal%5D)">Recipient outcomes with extended criteria donors using advanced heart preservation: an analysis of the GUARDIAN-Heart registry.</a> J Heart Lung Transplant. 43 (4), 673-680 (2024).</li>
<li>Ahmed, H. F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Donation+after+circulatory+death+significantly+reduces+waitlist+times+while+not+changing+post-heart+transplant+outcomes%3A+a+United+Network+for+Organ+Sharing+analysis%5BTitle%5D)+AND+%22J+Heart+Lung+Transplant%22%5BJournal%5D)">Donation after circulatory death significantly reduces waitlist times while not changing post-heart transplant outcomes: a United Network for Organ Sharing analysis.</a> J Heart Lung Transplant. 43 (3), 461-470 (2024).</li>
<li>Schroder, J. N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Transplantation+outcomes+with+donor+hearts+after+circulatory+death%5BTitle%5D)+AND+%22N+Engl+J+Med%22%5BJournal%5D)">Transplantation outcomes with donor hearts after circulatory death.</a> N Engl J Med. 388 (23), 2121-2131 (2023).</li>
<li>Schroder, J. N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Increasing+utilization+of+extended+criteria+donor+hearts+for+transplantation%3A+the+OCS+Heart+EXPAND+trial%5BTitle%5D)+AND+%22JACC+Heart+Fail%22%5BJournal%5D)">Increasing utilization of extended criteria donor hearts for transplantation: the OCS Heart EXPAND trial.</a> JACC Heart Fail. 12 (3), 438-447 (2024).</li>
<li>Mondal, N. K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Myocardial+edema%2C+inflammation%2C+and+injury+in+human+heart+donated+after+circulatory+death+are+sensitive+to+warm+ischemia+and+subsequent+cold+storage%5BTitle%5D)+AND+%22J+Thorac+Cardiovasc+Surg%22%5BJournal%5D)">Myocardial edema, inflammation, and injury in human heart donated after circulatory death are sensitive to warm ischemia and subsequent cold storage.</a> J Thorac Cardiovasc Surg. 167 (4), 1346-1358 (2024).</li>
<li>Ardehali, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Ex-vivo+perfusion+of+donor+hearts+for+human+heart+transplantation+%28PROCEED+II%29%3A+a+prospective%2C+open-label%2C+multicentre%2C+randomised+non-inferiority+trial%5BTitle%5D)+AND+%22Lancet%22%5BJournal%5D)">Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial.</a> Lancet. 385 (9987), 2577-2584 (2015).</li>
<li>Michel, S. G., LaMuraglia, G. M., Madariaga, M. L., Anderson, L. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Innovative+cold+storage+of+donor+organs+using+the+Paragonix+SherpaPak+devices%5BTitle%5D)+AND+%22Heart+Lung+Vessel%22%5BJournal%5D)">Innovative cold storage of donor organs using the Paragonix SherpaPak devices.</a> Heart Lung Vessel. 7 (3), 246-255 (2015).</li>
<li>Louca, J. O., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Outcomes+after+DCD+cardiac+transplantation%3A+an+international%2C+multicenter+retrospective+study%5BTitle%5D)+AND+%22JACC+Heart+Fail%22%5BJournal%5D)">Outcomes after DCD cardiac transplantation: an international, multicenter retrospective study.</a> JACC Heart Fail. 13 (1), 102473(2025).</li>
<li>Messer, S., Ardehali, A., Tsui, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Normothermic+donor+heart+perfusion%3A+current+clinical+experience+and+the+future%5BTitle%5D)+AND+%22Transpl+Int%22%5BJournal%5D)">Normothermic donor heart perfusion: current clinical experience and the future.</a> Transpl Int. 28 (6), 634-642 (2015).</li>
<li>Messer, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((A+5-year+single-center+early+experience+of+heart+transplantation+from+donation+after+circulatory-determined+death+donors%5BTitle%5D)+AND+%22J+Heart+Lung+Transplant%22%5BJournal%5D)">A 5-year single-center early experience of heart transplantation from donation after circulatory-determined death donors.</a> J Heart Lung Transplant. 39 (12), 1463-1475 (2020).</li>
<li>Hassanein, W. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Continuous+perfusion+of+donor+hearts+in+the+beating+state+extends+preservation+time+and+improves+recovery+of+function%5BTitle%5D)+AND+%22J+Thorac+Cardiovasc+Surg%22%5BJournal%5D)">Continuous perfusion of donor hearts in the beating state extends preservation time and improves recovery of function.</a> J Thorac Cardiovasc Surg. 116 (5), 821-830 (1998).</li>
<li>Dhital, K. K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Adult+heart+transplantation+with+distant+procurement+and+ex-vivo+preservation+of+donor+hearts+after+circulatory+death%3A+a+case+series%5BTitle%5D)+AND+%22Lancet%22%5BJournal%5D)">Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts after circulatory death: a case series.</a> Lancet. 385 (9987), 2585-2591 (2015).</li>
<li>Voigt, J. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Multicenter+registry+using+propensity+score+analysis+to+compare+a+novel+transport%2Fpreservation+system+to+traditional+means+on+postoperative+hospital+outcomes+and+costs+for+heart+transplant+patients%5BTitle%5D)+AND+%22ASAIO+J%22%5BJournal%5D)">Multicenter registry using propensity score analysis to compare a novel transport/preservation system to traditional means on postoperative hospital outcomes and costs for heart transplant patients.</a> ASAIO J. 69 (4), 345-349 (2023).</li>
<li>Silvestry, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Outcomes+in+heart+transplant+recipients+by+bridge+to+transplant+strategy+when+using+the+SherpaPak+cardiac+transport+system%5BTitle%5D)+AND+%22ASAIO+J%22%5BJournal%5D)">Outcomes in heart transplant recipients by bridge to transplant strategy when using the SherpaPak cardiac transport system.</a> ASAIO J. 70 (5), 388-395 (2024).</li>
<li>Kaliyev, R., Bekbossynov, S., Nurmykhametova, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Sixteen-hour+ex+vivo+donor+heart+perfusion+during+long-distance+transportation+for+heart+transplantation%5BTitle%5D)+AND+%22Artif+Organs%22%5BJournal%5D)">Sixteen-hour ex vivo donor heart perfusion during long-distance transportation for heart transplantation.</a> Artif Organs. 43 (3), 319-320 (2019).</li>
<li>Joshi, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Heart+transplantation+from+DCD+donors+in+Australia%3A+lessons+learned+from+the+first+74+cases%5BTitle%5D)+AND+%22Transplantation%22%5BJournal%5D)">Heart transplantation from DCD donors in Australia: lessons learned from the first 74 cases.</a> Transplantation. 107 (2), 361-371 (2023).</li>
<li>Rega, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Hypothermic+oxygenated+perfusion+of+the+donor+heart+in+heart+transplantation%3A+the+short-term+outcome+from+a+randomised%2C+controlled%2C+open-label%2C+multicentre+clinical+trial%5BTitle%5D)+AND+%22Lancet%22%5BJournal%5D)">Hypothermic oxygenated perfusion of the donor heart in heart transplantation: the short-term outcome from a randomised, controlled, open-label, multicentre clinical trial.</a> Lancet. 404 (10453), 670-682 (2024).</li>
<li>Lebreton, G., Leprince, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Successful+heart+transplant+after+12+h+preservation+aboard+a+commercial+flight%5BTitle%5D)+AND+%22Lancet%22%5BJournal%5D)">Successful heart transplant after 12 h preservation aboard a commercial flight.</a> Lancet. 403 (10431), 1019(2024).</li>
<li>McGiffin, D. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Hypothermic+oxygenated+perfusion+%28HOPE%29+safely+and+effectively+extends+acceptable+donor+heart+preservation+times%3A+results+of+the+Australian+and+New+Zealand+trial%5BTitle%5D)+AND+%22J+Heart+Lung+Transplant%22%5BJournal%5D)">Hypothermic oxygenated perfusion (HOPE) safely and effectively extends acceptable donor heart preservation times: results of the Australian and New Zealand trial.</a> J Heart Lung Transplant. 43 (3), 485-495 (2024).</li>
</ol>

The authors have no conflicts of interest to declare.

Hypothermia has been the gold standard for decades to achieve safe organ preservation. The optimal temperature for static cold storage ranges between 4 &#176;C and 8 &#176;C to prevent cellular damage. In experimental conditions, UCP can maintain a heart within this temperature range up to 30 h9. In our preliminary clinical experience, the longest ischemic time associated with UCP preservation was 286 min in a patient transplanted in emergency for post cardiotomy refractory heart failure. A severe...

Heart transplantation (HT) remains the treatment of choice for patients with advanced heart failure, despite advances in long-term mechanical circulatory support (MCS). Traditionally, donor heart preservation relies on ice-cold storage (ICS). In this method, the heart is first flushed with a crystalloid preservation solution, then stored in the same solution at 2-8 &#176;C using a three-bag system placed in a specialized icebox for organ transport.
However, this approach has several limitations. Significant temperature fluctuations have been reported during ICS, particularly overcooling (below +2 &#176;C), which may increase the risk of cold-induced graft injury. Additionally, ICS does not achieve complete hypothermic arrest of myocardial metabolism, which remains largely anaerobic. As a result, freeze-induced graft damage and subsequent ischemia-reperfusion injury are common. These injuries can contribute to primary graft dysfunction (PGD), especially when cold ischemic storage exceeds 4 h.
To minimize temperature fluctuations, uniform cooling preservation (UCP) using the SherpaPak Cardiac Transport System has been developed for the lungs, liver, and heart. Introduced in 2018, UCP provides consistent and controlled hypothermic preservation of the donor heart during transport, maintaining temperatures between 4 &#176;C and &#8239;&#176;C1. This technology aims to reduce the risk of freeze-induced graft injury. UCP has seen increasing adoption in Europe and North America, with over 40% of donor hearts in the United States transported using this method in 2023. The Cardiac Transport System is a single-use device with an outer transport shipper containing an internal battery that requires no external power source. Three cold ribbons, stored in a -20 &#176;C freezer for a minimum of 48 h, are then disposed of inside the outer transport shipper. A fourth cold ribbon is placed on the top of the outer canister. This device keeps the donor heart between 4 &#176;C and 8 &#176;C for a prolonged period of time (up to 8 h)2,3. The Cardiac Transport System provides UCP but without the possibility of active temperature regulation. The temperature is constantly monitored and can be observed on a mobile phone application via a secure Bluetooth connection. Geolocation of the device is also available during organ transportation, except during airplane flights.
A shortage of suitable donor hearts after brain death persists, despite the increasing use of marginal donors (e.g., age &#62; 55, prolonged cardiac arrest, or cardiovascular comorbidities). Donation after controlled circulatory death (DCD) has emerged as a promising strategy to expand the donor pool and has recently been associated with a significant reduction in waiting times for patients with advanced heart failure4,5,6. However, transplantations involving extended criteria donors (ECD) carry a higher risk of primary graft dysfunction (PGD), primarily due to prolonged warm ischemia and the potential for irreversible myocardial injury7. This underscores the need for improved preservation methods for ECD organs, as well as reliable assessment of myocardial viability prior to transplantation. Over the past decade, machine perfusion technology has emerged as an advanced modality for organ preservation. Normothermic ex-situ heart perfusion (ESHP) was initially developed to extend preservation times beyond the critical 4 h window associated with ice-cold storage (ICS)8. More recently, ESHP has demonstrated potential to expand the donor pool, particularly for ECD and DCD allografts5,9. Early clinical outcomes are comparable to those achieved with heart transplants from standard brain-dead donors5,10,11,12.
ESHP using oxygenated blood was first described in 199813. The Organ Care System (OCS) is the only commercially available device validated (FDA- and CE-marked) for the transportation of donor hearts in a normothermic perfused state. Immediately after retrieval, the donor heart is reperfused and maintained in a warm, beating state until arrival at the recipient center. Complementary materials (defibrillator, external pacemaker, transportable blood gas analyzer) and accessories (heart perfusion module, 9 V batteries, epicardial pacing leads, left ventricular vent, spare leukocyte-depleting filter) are necessary to allow ESHP with the transportable OCS device. The procurement team should be composed of a senior cardiac surgeon (the procurement surgeon), an assistant cardiac surgeon, and an intensivist, perfusionist, or another cardiac surgeon dedicated to managing the ESHP console throughout the procedure at the donor center. The donor&#39;s hematocrit should be greater than 25% (or hemoglobin &#62; 10 g/dL) to ensure optimal oxygen transport during ESHP.
The removable screen of the OCS console displays continuous values for mean aortic output and pressure, mean coronary flow, oxygen saturation, hematocrit, and temperature. Epinephrine infusion (diluted in 5% glucose solution) is used to maintain physiological levels of circulating catecholamines. This technology enables real-time visual and metabolic monitoring of the donor heart, allowing for assessment of its suitability for transplantation. A favorable ESHP is achieved when the arterial lactate trend is stable or decreasing, and this trend is consistent with a decreasing venous lactate concentration. A positive arterio-venous lactate difference confirms myocardial lactate extraction and serves as an accepted biomarker for optimal ESHP and donor heart eligibility for transplant8,13.
ESHP may increase the utilization rate of ECD, a major issue in the current setting of organ shortage. A recent emphasis has been observed in the past decade on the use of ESHP in DCD heart transplantation5,11,12,14. Indeed, Schroder et al. recently reported that 87% of donor hearts initially considered unsuitable for transplant (marginal donors) could finally be transplanted after ESHP6. Although promising, this technology is more complex than ICS and requires specialized technical skills that heart transplant teams must develop.
In our institution, we used exclusively ICS until 2019. We subsequently initiated an ESHP program for long-distance procurements and high-risk transplantations, particularly for recipients with preoperative mechanical circulatory support or a history of multiple open-heart surgeries. Since 2023, we have replaced ICS with uniform cooling preservation (UCP). The present protocol report aims to present a safe and reproducible methodology for implementing both ESHP and UCP. We also share our preliminary clinical experience in heart transplantation utilizing these two innovative technologies.

<table><tbody><tr><td>&lt;strong&gt;Equipment for OCS&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>4-0 polypropylene suture</td><td>Peters, bobigny, France&amp;nbsp;</td><td>20S15B</td><td>sutures</td></tr><tr><td>5-0 polypropylene suture</td><td>Peters, bobigny, France&amp;nbsp;</td><td>20S10B</td><td>sutures</td></tr><tr><td>Adrenaline 0.25 mg/L</td><td>Laboratoire Renaudin, Itxassou, France</td><td></td><td>Drugs for the Epinephrine infusion</td></tr><tr><td>Albumin 25% 100 mL</td><td>CSL Behring AG, Bern, Switzerland</td><td>44206-251-10</td><td>Drugs for the priming solution</td></tr><tr><td>Cefotaxime 1 g</td><td>Panpharma, Luitre, France</td><td>3400955083139</td><td>Drugs for the priming solution</td></tr><tr><td>Ciprofloxacin 200 mg</td><td>Panpharma, Luitre, France</td><td>3400893163542</td><td>Drugs for the priming solution</td></tr><tr><td>DLP Aortic Root Cannula</td><td>Medtronic Inc. Minneapolis, Minneapolis, USA</td><td>ref. 11012, 12.5 inch</td><td>Aortic Root Cannula</td></tr><tr><td>EKG epicardial electrodes&amp;nbsp;</td><td>Cardinal Health LLC, Waukegan, Illinois, USA</td><td>31050522</td><td>EKG detection electrodes&amp;nbsp;</td></tr><tr><td>External pacemaker</td><td>Medtronic Inc. Minneapolis, Minneapolis, USA</td><td>5392</td><td>Pacemaker device</td></tr><tr><td>Glucose 5%</td><td>B.Braun Melsungen AG, Melsungen, Germany</td><td>3400891780017</td><td>Drugs for the Epinephrine infusion</td></tr><tr><td>Heart Perfusion Set, Organ Care System</td><td>Transmedics, Andover, MA, USA</td><td>Ref#1200</td><td>Normothermic ex-vivo heart perfusion device</td></tr><tr><td>Insulin</td><td>Novo Nordisk, Puteaux, France</td><td>34009 352 590 9 7</td><td>Additive for the maintenance Solution</td></tr><tr><td>Intracardial sump&amp;nbsp;</td><td>Medtronic Inc. Minneapolis, Minneapolis, USA</td><td>12112</td><td>intracardial sump for left ventricle venting</td></tr><tr><td>Istat 1</td><td>Abbott, Chicago, Ill, USA</td><td>714336-03O</td><td>Blood Analyzer machine&amp;nbsp;</td></tr><tr><td>Methylprednisolone&amp;nbsp;</td><td>Mylan S.A.S, Saint Priest, France&amp;nbsp;</td><td>400005623</td><td>Drugs for the priming solution</td></tr><tr><td>Multivitamin Cernevit</td><td>BAXTER S.A.S, Guyancourt, France</td><td>34009 356 571 9 0</td><td>Drugs for the priming solution</td></tr><tr><td>OCS Aortic cannula&amp;nbsp;</td><td>TransMedics, Andover, USA</td><td>NA</td><td>Ex-situ heart perfusion aortic cannula&amp;nbsp;</td></tr><tr><td>OCS Pulmonary artery cannula&amp;nbsp;</td><td>TransMedics, Andover, USA</td><td>NA</td><td>Ex-situ heart perfusion pulmonary artery cannula&amp;nbsp;</td></tr><tr><td>Plegisol 1000 mL</td><td>Pfizer, Paris, France</td><td>34009 555 976 9 8</td><td>Cardioplegia</td></tr><tr><td>Sodium Bicarbonate</td><td>Laboratoire Renaudin, itxassou, France</td><td>3701447</td><td>Drugs for the priming solution</td></tr><tr><td>Sodium chloride</td><td>Aguettant, Lyon, France&amp;nbsp;</td><td>606726</td><td>Drugs for the priming solution</td></tr><tr><td>Two staged Venous Cannula (32 Fr)</td><td>Medtronic Inc. Minneapolis, Minneapolis, USA</td><td>91240, 32 french</td><td>Venous Cannula</td></tr><tr><td>&lt;strong&gt;Equipment for SHERPAPAK&lt;/strong&gt;</td><td></td><td></td><td></td></tr><tr><td>4-0 polypropylene suture</td><td>Peters, bobigny, France&amp;nbsp;</td><td>20S15B</td><td>sutures</td></tr><tr><td>5-0 polypropylene suture</td><td>Peters, bobigny, France&amp;nbsp;</td><td>20S10B</td><td>sutures</td></tr><tr><td>Perisoc 6 Litres</td><td>Serb laboratory, Paris, France&amp;nbsp;</td><td>34009 550 712 1 1</td><td>Cardioplegia</td></tr><tr><td>Sherpapak Aortic cannula&amp;nbsp;</td><td>Paragonix Technologies, Inc, Cambridge, Massachusetts, USA</td><td>NA</td><td>Static cold storage device</td></tr><tr><td>Sherpapak nested canister system</td><td>Paragonix Technologies, Inc, Cambridge, Massachusetts, USA</td><td>NA</td><td>Static cold storage device</td></tr><tr><td>Sherpapak Rigid Outer Shell</td><td>Paragonix Technologies, Inc, Cambridge, Massachusetts, USA</td><td>NA</td><td>Static cold storage device</td></tr><tr><td>Surgical Loop (coton)</td><td>B. BRAUN SURGICAL SA, Rubi (Barcelone), Spain</td><td>B1095668</td><td>sutures</td></tr></tbody></table>

innovative strategies for organ preservation in heart transplantation: uniform cooling preservation and ex-situ normothermic perfusion

Innovative Strategies for Organ Preservation in Heart Transplantation: Uniform Cooling Preservation and Ex-situ Normothermic Perfusion

Nearly 4,500 heart transplantations are performed annually worldwide. Given the current organ shortage, extended criteria are frequently accepted nowadays for the selection of donor hearts. There is therefore a need for optimized preservation technology to prevent the risk of primary graft dysfunction. The Uniform Cooling Preservation (UCP) is an FDA-approved and CE-marked approach applied in clinical practice since 2020. UCP provides stable cold storage for safe preservation of cardiac allografts, including those procured in donors with extended criteria. Decreased utilization of mechanical circulatory support, along with reduced hospital stay after transplant, has been associated with the use of UCP. Normothermic ex-situ heart perfusion (ESHP) has been developed to ensure safe and prolonged preservation of cardiac allografts. Thanks to ex-situ normothermic oxygenated blood perfusion, ESHP technology allows for continuous monitoring of the donor heart during transportation. Myocardial viability for transplant is characterized by a progressive decrease in lactate level in the perfusate. ESHP has recently been applied for the rehabilitation of cardiac allografts procured after controlled circulatory death. In the present report, we aim to describe technical features of UCP and ESHP preservation technologies. Early clinical outcomes will be discussed, focusing on the rate of severe primary graft dysfunction after transplant.

All consecutive heart transplantations performed in our institution between January 2020 and July 2023 were reviewed. Three groups were compared considering the approach for organ preservation: ice cold storage (ICS, n = 37), normothermic ex-situ heart perfusion (ESHP, n = 7), and uniform cooling preservation using the Uniform Cooling Preservation (UCP, n = 7). PDG was defined by either left ventricular ejection fraction &lt; 30%, and/or need for mechanical circulatory support (M...

Donor heart preservation is a major determinant of success in heart transplantation. Technological advances have led to optimizing the conditions of preservation, along with a more accurate assessment of the donor heart before transplantation. We herein describe two innovative technologies currently applied for cardiac preservation: uniform cooling preservation and normothermic ex-situ heart perfusion.

Nearly 4,500 heart transplantations are performed annually worldwide. Given the current organ shortage, extended criteria are frequently accepted nowadays ...

Heart transplantation is the treatment of choice for patients with advanced heart failure. Despite improvement in long-term mechanical circulatory support, historically, the standard technique for the preservation of the donor heart is ice-cold storage. The heart is first flushed with preservation solution and then maintaining the same solution between two and eight degrees Celsius.There are several limitations with this technique, temperature variation, and the remaining of an anaerobic metabolism that may cure lesions and lead to primary graft dysfunction. To avoid the temperature fluctuation, uniform cooling preservation has been developed and is increasingly used in Europe. Ex situ heart perfusion is the only commercially available device for transplantation of donor heart in normothermic perfusion states and has recently been demonstrated to expand the donor pool, especially for ECD and DCD allografts.Early outcomes are comparable with the results of heart transplantation with brain dead, non-marginal donors. To avoid temperature fluctuations, uniform cooling preservation has been developed by Paragonic Society. Retrieve the sterile-nested canisters, the outer one protects the inner one, and place the inner one in a cup filled with ice.A cold atmosphere is therefore created around the inner canister. Explant the donor heart conventionally with the longest possible ascending aorta to place the UCP-specific connector cannula high enough to preserve sufficient length for the aortic anastomosis. Choose the appropriate size for UCP aortic connector corresponding to the inner diameter of the ascending aorta.Secure the aortic cannula into the aortic lumen with an external surgical loop. Connect to the inner canister cover to suspend the donor heart in the preservation solution. Tear the inner canister, by slowly flushing the preservation solution through a dedicated port.Fluid will exit from a second port located on the cover. Fill the canister with solution up to the top, then close it with its dedicated cap. Ensure the donor heart is completely submerged in the preservation solution.Then, place the inner canister inside the outer canister. Lock the outer canister with its dedicated cover. Place the outer canister in the shipper and start temperature monitoring.Read the preservation temperature on the anterior screen of the shipper and on the mobile phone application. No temperature adjustment is possible during organ transportation using UCP. The organ care system developed by TransMedics is the only commercially available device validated for transportation of hearts in normothermic perfused state.Cannulate the right atrium with a 32 French double-staged cannula. Connect a sterile heparinized bag, 10, 000 IU, to the right atrium cannula and collect 1, 200 to 1, 500 milliliters of blood. Allow 90 to 120 seconds for this process.Place the heart in a sterile cup with four degrees Celsius saline solution. Place four pledgeted 4.0 monofilament sutures at the cardinal points of the distal ascending aorta. Choose the appropriate aortic cannula among the four sizes to fit with the diameter of the donor aorta.Do not oversize the cannula. Secure the aortic cannula with an external cable tie to prevent accidental detachment of the heart from the connector during transport. Secure the malleable pulmonary cannula with a 4.0 monofilament running suture around the pulmonary trunk.Create a purse-string suture with 4.0 monofilament on the left atrium to secure the left ventricular vent cannula. Insert the cannula into the left ventricle through the left atrium to allow de-airing during ESHP. Reduce the pump flow to 1, 000 milliliters per minute and remove the shunt between the aortic and venous lines before positioning the heart.Place the heart upside down with posterior ventricular walls in front of the operator. De-air the ascending aorta and connect the aortic cannula to the aortic line. Perform a gentle cardiac massage until the heart is warmed up.Deliver a 30 joules shock in case of ventricular fibrillation to obtain a sinus rhythm. Close the inferior vena cava with a 4.0 monofilament running suture. At this point, all the deoxygenated blood flowing from the coronary sinus goes into the right atrium and is ejected through the pulmonary artery since the right ventricle is beating.De-air and connect the pulmonary cannula to the venous line. Place an epicardial pacing lead on the posterior wall of the right ventricle. Connect this lead to an external pacemaker and pace the heart at 80 beats per minute.Once connected on the perfusion module, the isolated heart thus receives a warm 34 degrees Celsius oxygenated and nutrient-enriched perfusion. All consecutive heart transplantations performed in our institution between January 2020 and July 2023 were reviewed. Three groups were compared considering the approach for organ preservation:ice-cold storage, normothermic ex situ heart perfusion, and uniform cooling preservation using the uniform cooling preservation.Primary graft dysfunction was defined by either left ventricular ejection fraction less than 30%and/or need for mechanical circulatory support within 24 hours after transplant, and/or need for urgent re-transplant during the hospital stay. Mean recipient age was 45.1 years without any difference between groups. Similarly, the indication for transplant and mean time on the waiting list was not statistically different between groups.45%of patients were referred for transplant under mechanical circulatory support. Nine transplantations were combined with either Kidney 4 or Liver 5 transplant. Mean donor age was 42.7 years without difference between groups.The median ischemic time for the donor heart was 195 minutes in ICS group, 113 minutes in ESHP group, and 247 minutes in UCP group. Postoperative high sensitivity cardiac troponin T was significantly lower in uniform cooling preservation group compared to ice-cold storage and ex situ heart perfusion groups. The rate of severe PGD was 27%in ICS group, 43%in ESHP group, and 14%in UCP group.The need for temporary ECMO after transplant was observed in 42%of cases in ICS group, 71%in ESHP group, and 14%in UCP group. Median length of stay in intensive care unit was significantly lower in UCP group. Six-month survival rate was not different between groups.Uniform cooling preservation and ex situ heart perfusion have opened a new era in heart transplantation. These approaches ensure optimized preservation of the donor heart to prevent several primary graft dysfunction. This is a major improvement in the current setting of donors with extended criteria and more challenging recipients refer to heart transplantation.By minimizing cold-induced myocardial damages and ischemia-reperfusion injuries, this technology are already associated with improved clinical outcomes. The future of organ preservation will undoubtedly involve a multimodal strategy including these technologies.

innovative-strategies-for-organ-preservation-heart-transplantation

Research

JoVE Journal

Medicine

Marginal grafts, such as fatty livers, grafts from older donors, or livers retrieved after cardiac death (DCD) tolerate conventional, cold static storage only poorly. We developed a novel model of subnormothermic ex vivo liver perfusion for preservation, assessment, and repair of marginal liver grafts prior to transplantation.

Technique of Subnormothermic Ex Vivo Liver Perfusion for the Storage, Assessment, and Repair of Marginal Liver Grafts

Here we present a protocol describing oxygenated ex situ machine perfusion of donor liver grafts. This article contains a step by step protocol to procure and prepare the liver graft for machine perfusion, prepare the perfusion fluid, prime the perfusion machine and perform oxygenated normothermic machine perfusion of the liver graft.

Ex Situ Normothermic Machine Perfusion of Donor Livers

We describe a method of ex vivo machine perfusion of human liver grafts at subnormothermic temperature (21 °C).

Functional Human Liver Preservation and Recovery by Means of Subnormothermic Machine Perfusion

The severe organ shortage has resulted in increased use of marginal kidney grafts for transplantation. This has triggered interest in alternative storage methods, since marginal grafts especially tolerate cold storage poorly. The technique of normothermic ex vivo kidney perfusion (NEVKP) represents a novel preservation method for kidney grafts prior to  transplantation.

Normothermic Ex Vivo Kidney Perfusion for the Preservation of Kidney Grafts prior to Transplantation

Normothermic ex situ heart perfusion (ESHP), preserves the heart in a beating, semi-physiologic state. When performed in a working mode, ESHP provides the opportunity to perform sophisticated assessments of donor heart function and organ viability. Here, we describe our method for myocardial performance evaluation during ESHP.

Normothermic Ex Situ Heart Perfusion in Working Mode: Assessment of Cardiac Function and Metabolism

We present a protocol for utilizing a normothermic ex vivo sanguinous perfusion system for the delivery of therapeutics to an entire cardiac allograft in a porcine heterotopic heart transplant model.

A Porcine Heterotopic Heart Transplantation Protocol for Delivery of Therapeutics to a Cardiac Allograft

A reliable noninvasive approach for functional assessment of the donor heart during normothermic ex situ heart perfusion (NESP) is lacking. We herein describe a protocol for ex situ assessment of myocardial performance using the epicardial echocardiography and conductance catheter method.

Functional Assessment of the Donor Heart During Ex Situ Perfusion: Insights from Pressure-Volume Loops and Surface Echocardiography

Here, we present an assessment protocol of a heterotopically implanted heart after normothermic ex situ preservation in the rat model.

Rat Model of Normothermic Ex-Situ Perfused Heterotopic Heart Transplantation

We describe an ex vivo isolated working rat heart protocol to test donor heart preservation strategies. This paper describes the protocol for use in static cold storage of rodent donor hearts; however, the protocol can also be used for donor hearts obtained after donation after circulatory death and brain death.

Using an Isolated Working Rat Heart Model to Test Donor Heart Preservation Strategies

There is a significant liver donor shortage, and criteria for liver donors have been expanded. Normothermic ex vivo liver perfusion (NEVLP) has been developed to evaluate and modify organ function. This study demonstrates a rat model of NEVLP and tests the ability of pegylated-catalase, to mitigate liver preservation injury.

A Small Animal Model of Ex Vivo Normothermic Liver Perfusion

Learn innovative heart preservation techniques including uniform cooling and ex-situ normothermic perfusion for cardiac transplantation. These methods reduce temperature variation and expand the donor pool to improve transplant outcomes.

Innovative Strategies for Organ Preservation in Heart Transplantation: Uniform Cooling Preservation and Ex-situ Normothermic Perfusion (Video) | JoVE Journal

Innovative Strategies for Organ Preservation in Heart Transplantation: Uniform Cooling Preservation and Ex-situ Normothermic Perfusion

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