Rapid recovery of donor allograft(s) with extended ultra-oxygenated preservation

Abstract

Rapid recovery with extended ultra-oxygenated preservation (REUP) can ethically and cost-effectively improve recovery and transplant outcomes for donation after circulatory death (DCD) allografts. REUP can include a portable system, method, and specialized ultra-oxygenated solution(s). The portable system includes a flush circuit and at least one cannula connected to the DCD allograft for flushing the ultra-oxygenated solution into the in-situ DCD allograft. The flush circuit can include at least one reservoir for the ultra-oxygenated solution, a temperature control device, a pressure regulation system, optionally an oxygenator, and tubing for connecting components. The system is noted as easily portable and cost effective for use in many conditions, including environments where traditional recovery systems cannot be used. The methods and solution can be specialized depending on donor demographic information, previous surgeries, and / or allograft type.

Description

NONPROVISIONALRAPID RECOVERY OF DONOR ALLOGRAFT(S) WITH EXTENDED ULTRAOXYGENATED PRESERVATIONCross-Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Application Serial No.63 / 742,257, filed 7 January 2025, entitled “IN SITU RESUSCITATION DURING DONOR ORGAN RECOVERY USING CUSTOM OXYGENATED PERFUSATES AND PORTABLE PERFUSION SYSTEMS”, and also claims the benefit of U.S. Provisional Application Serial No. 63 / 826,572, filed 19 June 2025, entitled “RAPID RECOVERY OF DONOR ALLOGRAFT(S) WITH EXTENDED ULTRA-OXYGENATED PRESERVATION”. The entirety of these provisional applications are incorporated by reference for all purposes.Technical Field

[0002] The present disclosure relates generally to allograft recovery, and more specifically to rapid recovery of donor allograft(s) with extended ultra-oxygenated preservation (REUP).Background

[0003] There is a worldwide lack of viable allografts (e.g., organs, limbs, tissues, etc.) for transplantation. When an allograft does become available, significant bottlenecks exist, arising from insufficient recovery methods. One such recovery method is Donation after Circulatory Death (DCD), which traditionally utilizes either direct procurement and perfusion (DPP) or normothermic regional perfusion (NRP). DPP is extraordinarily costly, complicated, and labor intensive, often with mediocre outcomes. NRP is more affordable and has superior outcomes compared to DPP but has been prohibited by many hospitals, organ procurement organizations, and countries due to ethical controversies regarding re-animation of donor organs.Summary

[0004] Rapid recovery of an in-situ donor allograft(s) with extended ultraoxygenated preservation (REUP) is an ethical donation after circulatory death (DCD) allograft recovery method compared to normothermic regional perfusion (NRP) that can provide outcomes that are superior to direct procurement and perfusion (DPP). A specialized ultra-oxygenated solution can be prepared and flushed through a DCD allograft while the DCD allograft is still in the DCD donor to maintain and / or improve the life-span and viability of the allograft for transport and transplant.

[0005] In an aspect, the present disclosure can include a portable system for rapid recovery with extended ultra-oxygenated preservation of a DCD allograft in situ in the donor. The system can include a flush circuit and at least one cannula. The flush circuit can be configured to flush an ultra-oxygenated solution through a DCD allograft to preserve the DCD allograft for transplantation. The flush circuit can include: a reservoir configured to hold the ultra-oxygenated solution, tubing configured to connect the reservoir to the DCD allograft, a temperature control device configured to maintain the ultra-oxygenated solution at a temperature, and a pressure regulation system configured to flow the ultra-oxygenated solution into the DCD allograft at and / or near a pressure (e.g., a predetermined pressure). The flush circuit can also include an oxygenator configured to oxygenate the ultra-oxygenated solution, if not preoxygenated. The at least one cannula can be configured to be positioned in an artery of the DCD allograft to connect the tubing of the flush circuit with the DCD allograft for administration of the ultra-oxygenated solution to the DCD allograft.

[0006] In another aspect, the present disclosure can include a method for rapid recovery of a DCD allograft from a DCD donor. At least one artery of the DCD allograft can be cannulated within the DCD donor. An ultra-oxygenated solution can be flushed through the DCD allograft at a pressure (e.g., a predetermined pressure) for a time with a system comprising a flush circuit. The DCD allograft can then be extricated from the DCD donor for transplantation. The method can resuscitate the DCD allograft without reanimation of the DCD allograft or systemic circulation of the donor.Brief Description of the Drawings

[0007] The foregoing and other features of the present disclosure will become apparent to those skilled in the art to which the present disclosure relates upon reading the following description with reference to the accompanying drawings, in which:

[0008] FIG. 1 is a block diagram of a portable system for rapid recovery of a donation after circulatory death (DCD) allograft with extended ultra-oxygenated preservation;

[0009] FIG. 2 is a schematic diagram of an example portable system of FIG. 1 ;

[0010] FIG. 3 is a block diagram of a controller that can be used with the system of FIG. 1 to regulate perfusate inflow pressure;

[0011] FIG. 4 shows illustrations of various example dual lumen cannulas that can be part of the system of FIG. 1 ;

[0012] FIG. 5 is a process flow diagram showing a general method for rapid recovery of a DCD allograft with extended ultra-oxygenated preservation;

[0013] FIGS. 6-8 are process flow diagrams showing methods for rapid recovery of specific DCD allografts with extended ultra-oxygenated preservation;

[0014] FIG. 9 is a process flow diagram showing a method for pressure regulation for rapid recovery of specific DCD allografts with extended ultra-oxygenated preservation;

[0015] FIG. 10 is an illustration of an example system; and

[0016] FIGS. 11-13 are illustrations and photographs of example components of the system of FIG. 10.Detailed DescriptionI. Definitions

[0017] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure pertains.

[0018] As used herein, the singular forms “a,” “an”, and “the” can also include the plural forms, unless the context clearly indicates otherwise.

[0019] As used herein, the terms “comprises” and / or “comprising,” can specify the presence of stated features, steps, operations, elements, and / or components, but donot preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups.

[0020] As used herein, the term “and / or” can include any and all combinations of one or more of the associated listed items.

[0021] As used herein, the terms “first,” “second,” etc. should not limit the elements being described by these terms. These terms are only used to distinguish one element from another. Thus, a “first” element discussed below could also be termed a “second” element without departing from the teachings of the present disclosure. The sequence of operations (or acts / steps) is not limited to the order presented in the claims or figures unless specifically indicated otherwise.

[0022] As used herein, the term “donation after circulatory death (DCD)” refers to a type of allograft retrieval for the purpose of transplantation where the allograft is recovered from a donor whose circulatory and respiratory functions have stopped and / or cannot function on their own. In some instances, DCD can also be used to describe the donor and / or the allograft in this process.

[0023] As used herein, the term “flush circuit” refers to a path that blood, a manmade perfusate, or the like, flows through to supply oxygen, nutrients, medication, or the like to one or more allografts while the one or more allografts are still connected to the donor.

[0024] As used herein, the term “allograft” and “DCD allograft” can be used interchangeably to refer to an organ, tissue, limb, cells, or the like that can be transplanted from a donor to a recipient. An allograft can include but is not limited to an internal organ (e.g., heart, liver, lungs, kidney, pancreas, small intestine, gut, etc.), an external organ (e.g., skin), tissue, a bioengineered graft, a xenogenic organ graft, a limb (e.g., arm, leg, hand, foot, finger, etc.), or the like.

[0025] As used herein, the term “donor” and “DCD donor” can be used interchangeably to refer to an organism (e.g., a patient) whose heart has stopped beating and death has been declared using cardiorespiratory criteria, but who are not brain dead. Often, the organism has sustained a permanent brain injury that results in necessary life-sustaining medical treatment and / or ventilated support. One example of aDOD donor is a patient whose brain or circulatory system is too damaged to recover, but has minimal function, and cannot survive without ventilator or circulatory support.

[0026] As used herein, the term “recipient” refers to an organism (e.g., a patient) that receives an allograft from a donor and undergoes the transplant process.

[0027] As used herein, the term “ultra-oxygenated solution” refers to a preservation solution that can be flushed through a DCD allograft at a pressure for a time prior to recovery surgery, transport, and then transplantation to improve recovery and overall transplant outcomes. The ultra-oxygenated solution can include, but is not limited to, a perfusate, a crystalloid solution, cross packed red blood cells, and various additives for improving metabolic outlook and preventing inflammation and / or injury, that are oxygenated before use.

[0028] As used herein, the term “perfusate” refers to a fluid comprising nutrients, substrates, metabolites, electrolytes, and an oxygen carrier that is perfused through a detached biological tissue to preserve the function and viability of the detached biological tissue. Examples perfusate can include, but is not limited to, cardioplegias such as del Nido cardioplegia, University of Wisconsin (UW) solution, Perfadex® solution, histidine-tryptophan-ketoglutarate (HTK), or the like.

[0029] As used herein, the term “cross packed red blood cells” refers to red blood cells that have undergone a cross match test to ensure that the red blood cells are compatible with the recipient’s blood type to minimize the risk of transfusion reactions.

[0030] As used herein, the term “physiologic stability” refers to a dynamic state in a living organism where one or more physiological parameters are maintained within a specific range, even in the face of potential disturbances. Physiologic stability characterizes normal function of an organism, and / or one or more organs that make up the organism, not suffering from disease or injury. Physiological parameters can include, but are not limited to, oxygen saturation, pressure, temperature, and pH level.

[0031] As used herein, the term “patient” can refer to any warm-blooded organism including, but not limited to, a human being, a pig, a rat, a mouse, a dog, a car, a goat, a sheep, a horse, a monkey, an ape, a rabbit, a cow, etc. It should be noted that a patient is a type of organism.II. Overview

[0032] Transplantation suffers from a shortage of viable allografts (e.g., organs, limbs, tissues, etc.). When a donor allograft does become available, this shortage is made more evident due to significant bottlenecks arising from insufficient recovery methods when a donor allograft does become available. Donation after Circulatory Death (DCD) is one common recovery method. DCD allografts are typically recovered with either direct procurement and perfusion (DPP) or with normothermic regional perfusion (NRP). DPP involves the use of commercially available ex-situ devices that are complicated, labor intensive, and extraordinarily costly. DPP also cannot provide resuscitation of the abdominal organs. Compared to DPP, NRP is more affordable, increases organ yield, and has been shown to have superior outcomes in heart and abdominal organ transplantations. However, NRP is the subject of ethical controversy and prohibited by many hospitals, organ procurement organizations, and countries. Many of the ethical controversies are due to re-animating the heart in the donor, which is required by NRP.

[0033] To remedy the inherent limitations of both DPP and NRP, and provide acceptable transplant outcomes, a technique was developed to allow for rapid recovery of allografts from a DCD donor (referred to as Rapid recovery with extended ultraoxygenated preservation (REUP)). REUP simplifies the allograft recovery process, has significant economic advantages, and can improve access to transplantation in regions with limited resources. Moreover, REUP removes ethical concerns by only flushing oxygenated preservation solution to the donor allograft (e.g., heart) without reanimation of the heart or systemic circulation and, for the heart, does not require clamping of the aortic arch vessels. REUP uses an innovative preservation solution mixture that is ultraoxygenated to restore the energy debt incurred by tissue of the donor organ during the donor’s dying process. The preservation of REUP is flushed through the donor organ for an extended time and uses temperature and pressure based-regulation of the flush for improved outcomes (e.g., targeting 4°C (plus or minus 4°C), from 10°C to 12°C (plus or minus 2°C), or the like and aortic pressure of 80 mmHg (plus or minus 20 mmHg) for a heart). The extended duration of the flush allows for physiologic coronary perfusion to prevent endothelial damage that may occur with shorter duration high pressureinfusions. REUP purposefully does not re-animate the donor organ (e.g., heart) using del Nido cardioplegia as a base to ensure the donor organ (e.g., the heart) remains in a relaxed, arrested state. It should be understood that while REUP is described with respect to DCD donor(s) and allograft(s), REUP can also be used with other types of donors and allografts, such as a donation after brain death (DBD) donor(s) and allograft(s).III. Systems

[0034] Donation after circulatory death (DCD) donors have been steadily increasing since the mid-1990’s, but a significant shortage of allografts for transplant still remains. Rapid recovery with extended ultra-oxygenated preservation (REUP) simplifies the allograft recovery process in an ethical, cost effective, and safe and effective manner. Furthermore, REUP can be employed in many environments and does not require significant power to run and / or take up excess space (like current machine perfusion options). The ability to effectively recover and maintain viability of allografts from DCD donors is a significant improvement in transplant technology. While a DCD donors and allografts are described herein, it should be understood that the system(s) can be utilized with respect to other types of donors and allografts, including, but not limited to donation after brain death (DBD) donors and DBD allografts.

[0035] An aspect of the present disclosure can include a system 100 (FIG. 1) that can be used for REUP to recover a DCD allograft from a DCD donor in-situ. The system 100 can provide ultra-oxygenated solution (also referred to as the solution) to the DCD allograft for resuscitation without reanimation of the DCD allograft or systemic circulation of the donor. The system 100 can be portable (e.g., of movable weight and / or includes wheels, handles, or the like for larger components (not shown for ease of illustration)). The system 100 can include a flush circuit 102 in fluid communication (e.g., via tubing 110) with at least one cannula (e.g., cannula(s) 114) attached to at least one artery of a DCD allograft in situ in a DCD donor. The flush circuit 102 can flush an ultraoxygenated solution through the DCD allograft (via the cannula(s) 114) to preserve the DCD allograft for recovery and transplantation. The ultra-oxygenated solution can be a solution configured to improve a metabolic outlook and prevent inflammation and / orinjury of the DCD allograft. The ultra-oxygenated solution, which can include cross packed red blood cells, del Nido cardioplegia, and other components, can be oxygenated from 21% to 100% fraction of inspired oxygen (FIO2) for a time prior to flushing, and can be set to a pH (e.g., 7.50).

[0036] The flush circuit 102 can include at least one reservoir (e.g., reservoir(s) 104) and tubing 110 (e.g., medical grade tubing and necessary connectors) to connect at least one of the reservoir(s) to the cannula(s) 114. The reservoir(s) 104 can hold the ultra-oxygenated solution. Depending on the volume of the reservoir(s) 104 and the volume of the ultra-oxygenated solution all of the solution can be held in a single reservoir and / or can be split between multiple reservoirs that can be in removable and / or continuous fluid communication with each other. The reservoir(s) 104 can be a closed container (e.g., with a lid and / or a closeable opening), for instance, a pressure bag with or without a pressure regulator. The ultra-oxygenated solution can be premixed, mixed in the reservoir(s) 104, and / or oxygenated in the reservoir(s).

[0037] The flush circuit 102 can also include a temperature control device 106 and a pressure regulation system 108. The temperature control device 106 can maintain the ultra-oxygenated solution at a temperature and / or within a temperature range (e.g., from 4°C to 12°C). The temperature control device 106 can be, for instance, a heat exchanger, one or more cooling devices, a heater, or the like. The temperature control device 106 can include a temperature sensor (e.g., thermometer, a thermocouple, a thermistor, or the like) that can be positioned in the reservoir(s) 104 and / or the tubing 110 to check the temperature of the solution at a given time. In some instances, the temperature control device 106 can include a controller that can automatically keep the temperature within the desired range based on sensed temperature and set limits (e.g., with feedforward and / or feedback control, FID control, or the like). The pressure regulation system 108 can control the flow rate of the ultra-oxygenated solution (e.g., from 80 CC / min to 300 CC / min for an adult donor, from 30 CC / min to 200 CC / min for a pediatric donor) into the DCD allograft at and / or near a desired pressure (e.g., from 50 mmHg to 120 mmHg, from 60 mmHg to 80 mmHg, or the like). The pressure regulation system 108 can include, for instance a pressure sensor configured to measure a pressure of the ultra-oxygenated solution at a location in the flush circuit 104, a flowregulator configured to regulate the flow rate of the ultra-oxygenated solution, and / or a pump to alter pressures / flow rates depending on the configuration of system 100. In some instances, the flush circuit 102 can also include an oxygenator 112 that can oxygenate (or further oxygenate, in some instances) the solution within the reservoir(s) 104. The oxygenator 112 can oxygenate the solution from 21% to 100% fraction of inspired oxygen for a time (e.g., 5 minutes to 20 minutes). The oxygenator 112 can include, for example, an oxygen tank (can be mini), a carbon dioxide tank (can be mini), and a splitter that can allow for adjustment of the levels of PO2 (e.g., by adding / removing O2 from the solution), pH (e.g., by removing adding CO2 from the solution) or the like.

[0038] FIG. 2 shows an illustration of an example of system 100. It should be understood this example is not intended to be limiting. In this illustration, the system 100 can include reservoir 104 that can hold the ultra-oxygenated solution. The reservoir 104 can, for instance, take the shape of a pressure bag hung above the donor and / or the surgical space. The reservoir 104 can be connected to an oxygenator 112 that can oxygenate the solution(e.g., a value from 21 % to 100% fraction of inspired oxygen). The oxygenator 112 can include at least a carbon dioxide tank 202 that can receive carbon dioxide from the solution and an oxygen tank 204 that can provide oxygen to the solution. In some instances, the carbon dioxide tank 202 and / or the oxygen tank 204 can be a mini (easily transportable) tank. The oxygenator 112 can be connected to the reservoir by tubing 110. The carbon dioxide tank 202 can also add or remove carbon dioxide from the solution (with the use of bi-directional pressure regulation) to alter the pH of the solution. A temperature control device 106 (e.g., temperature sensor and / or control device) can be connected to the reservoir 104 and / or in line with a portion of the tubing 110 to control the temperature of the solution before the solution can be flushed through the DCD allograft. The temperature can be, for instance, maintained between 4°C and 12°C.

[0039] The system 100 can then include a pressure regulation system 108 that can be in line with tubing connecting the reservoir 104 and the cannula(s) 114(1 )-(N). The pressure regulation system 108 can include at least one sensor (e.g., sensor(s) 206 that can measure pressure and / or flow rate within the system 100. The sensor(s) 206 can bepositioned in tubing 110 near (as shown) the cannula(s) 114(1 )-(N) and / or within the cannula(s). The sensor(s) 206 can measure one or more of pressure, flow, pH, temperature, chemical compositions of the solution, or the like. The sensor(s) 206 can measure, for instance, root vent pressure, also referred to as inflow pressure of the ultra-oxygenated solution. The root vent pressure range can be, for example, from 40 mmHg to 120 mmHg, 60 mmHg to 100 mmHg, 60 mmHg to 80 mm Hg, or the like. The pressure regulation system 108 can further include a flow regulator 208 that can be adjusted to control the flow rate of the solution into the cannula and the DCD allograft. The flow rate can be maintained at ranges, for instance, from 80 CC / min to 300 CC / min for an adult, 30 CC / min to 200 CC / min for a pediatric patient, or the like. The flow regulator 208 can alter the flow rate in response to the measured pressure being outside a predetermined boundary (e.g., by mechanical and / or automatic means) (e.g., feedforward control laws, feedback control laws, PID control laws, or the like). For example, the flow regulator 208 can be a pinch valve (however, it will be understood that other types of valves and / or flow regulators can be used). The pressure regulation system 108 can also include, in some instances, at least one pump (e.g., pump(s) 210). The pump(s) 210 can assist in regulating flow rate of the solution to the DCD allograft. In some instances, a controller 212 can be in communication with one or more components of the pressure regulation system 108 for regulating the inflow pressure (discussed in more detail with respect to FIG. 3). In other instances, the controller 212 may not be necessary.

[0040] The cannula(s) 114(1 )-(N) each can be positioned within an artery of the DCD allograft. The cannula(s) 114(1 )-(N) can connect the tubing 110 of the system 100 (e.g., the flush circuit 102) with the DCD allograft for administration of the solution to the DCD allograft while the DCD allograft is still within the donor. The cannula(s) 114(1 )-(N) can be one or more cannulas depending on the number of inflow arteries of a DCD allograft. At least one cannula can be positioned in at least one immediate inflow artery of the DCD allograft. If the DCD allograft is a heart, then one cannula can be positioned in an aortic root. If the DCD allograft is a lung, then one cannula can be positioned in a pulmonary artery. If the DCD allograft is a liver and / or a kidney, then one cannula can be positioned in an abdominal aorta. In some instances, the cannula(s) 114(1 )-(N) canbe dual lumen cannula(s) (as discussed in more detail with respect to FIG. 4) The system 100 can flush at least one liter (from one liter to six liters) of the solution through the cannula (e.g., aortic root needle for the heart, or the like) into the DCD allograft at a flow rate (that can be fixed and / or variable) from 120 CC / min to 250 CC / min (or more broadly from 100 CC / min to 300 CC / min for an adult donor or from 30 CC / min to 200 CC / min for a pediatric donor) for a time period from 4 minutes to 30 minutes. For example, the system 100 can flush the solution through the DCD heart at a rate of 200 mL / min for a time period from 10 to 20 minutes such that an aortic root pressure of the delivered solution is 80 mmHg (plus or minus 20 mmHg).. The system 100 can provide the ultra-oxygenated solution to the DCD allograft for resuscitation without reanimation of the DCD allograft or systemic circulation of the donor (e.g., removing ethical concerns). With this, the system 100 can allow for rapid recovery of the DCD allograft with improved viability and recovery outcomes.

[0041] FIG. 3 shows an example of a controller 212 in communication with at least a portion of a pressure regulation system (e.g., 108 as shown in FIG. 2). The controller 212 can include a non-transitory memory (e.g., memory 302) that can store instructions for regulating an inflow pressure of the ultra-oxygenated solution and a processor 304 that can execute the instructions for regulating the inflow pressure of the ultraoxygenated solution. The memory 302 and processor 304 can be embodied as separate components or as a combined component (e.g., a microprocessor). The controller 212 can include and / or be in communication with one or more user interfaces (not shown) (e.g., a touch screen, buttons, computer mouse, or the like) for receiving inputs from a user and / or a display (also not shown) for outputting at least pressure information (e.g., visual display, audio output, or the like). The instructions can include set 306 for setting a preferred perfusion inflow pressure (e.g., from 60 mmHg to 80 mmHg) (which may depend on the DCD allograft - size, type, health information, etc.). The preferred perfusion inflow pressure may alternatively be pre-set. During the perfusion protocol the controller can include the instructions to receive 308 a measurement of the inflow pressure of the ultra-oxygenated solution into the DCD allograft from sensor(s) 206 (e.g. positioned in a cannula of the flush circuit connected to the DCD allograft); determine 310 a difference between the pressure measurementand a desired inflow pressure of the ultra-oxygenated solution into the DOD allograft; and adjust 312 the inflow pressure via pressure regulator(s) 208 to reach the desired inflow pressure in response to the measured inflow pressure being outside a predetermined boundary (e.g., 1 mmHg different, 2 mmHg different, 5 mmHg different, or the like). In one example, the sensor(s) 206 can be pressure sensors and the flow regulator(s) 208 can be pinch valves that can be at least partially opened and / or closed by the controller 212 to alter the flow rate of the ultra-oxygenated solution.

[0042] FIG. 4 shows example diagrams of dual lumen cannula 402 that can be used as one or more cannula(s) 114. As an example, the dual lumen cannula 402 can be connected from the flush circuit 102 to an inflow artery of a DCD allograft (e.g., cannulated). FIG. 4, element A shows an example of dual lumen cannula 402 (e.g., an example of a cannula 114) that can be cannulated to an inflow artery of a DCD allograft and connected to a flush circuit 102 via a flow regulator 208. The dual lumen cannula 402 can have a flange 404 connecting the dual lumen cannula to the DCD allograft and / or facilitating holding the two lumens together. One or more sensor(s) 206 can be positioned in and / or on a portion of the dual lumen cannula 402 to measure the pressure of the ultra-oxygenated solution just prior to the solution entering the DCD allograft (e.g., providing a real time and accurate measure of inflow pressure compared to relying on the flow rate assumed from a pressure bag). The one or more sensor(s) 206 can be in communication (wired and / or wireless) with controller 212 to send the measurements (e.g., at a frequency) for the controller to closed-loop regulate the flow through the flow regulator 208 (in wireless and / or wired communication with the controller).

[0043] FIG. 4, element B shows an example of a cut view of a side-by-side dual lumen cannula 402 and FIG. 4, element C shows an example of a cut view of an interior-exterior dual lumen cannula 402 (which could be concentric but need not be concentric). In FIG. 4, element B the perfusate infusion lumen 406 can be side by side with the pressure read out lumen 408. The ultra-oxygenated solution can be flowed through the perfusate infusion lumen 406, without a sensor 206 disrupting the flow or adding a non-sterile element. And the sensor(s) 206 can be positioned in the pressure read out lumen 408. The sensor(s) 206 can be any type of pressure sensor (e.g.,gauge, differential, piezoresistive, capacitive, piezoelectric, or the like). The sensor(s) 206 can be positioned within the pressure read out lumen 408 near and / or adjacent to the perfusate infusion lumen 406. The perfusate infusion lumen 406 and the pressure read out lumen 408 can be the same size and / or different sizes and the pressure read out lumen can be configured to truncate prior to the cannulation and / or can be cannulated with the perfusate infusion lumen into the DCD allograft. In FIG. 4, element C the perfusate infusion lumen 410 is positioned within a pressure readout lumen 412 (the lumens can be concentric and / or offset). While not shown it should be understood that perfusate infusion lumen 410 can also be the external lumen. The ultra-oxygenated solution can be flowed through the perfusate infusion lumen 410, without a sensor 206 disrupting the flow or adding a non-sterile element. The sensor(s) 206 can be positioned in the pressure read out lumen 412 and can be any type of pressure sensor (e.g., gauge, differential, piezoresistive, capacitive, piezoelectric, or the like). The sensor(s) 206 can be positioned within the pressure read out lumen 412 near and / or adjacent to the perfusate infusion lumen 410. In one example, the sensor 206 can be wrapped at least partially around the perfusate infusion lumen 410. The perfusate infusion lumen 410 can be configured to extend with an open end into the DCD allograft (at the cannulation) and the pressure read out lumen 412 can be configured to truncate prior to the cannulation and / or can be cannulated with the perfusate infusion lumen into the DCD allograft.IV. Methods

[0044] Another aspect of the present disclosure can include methods 500, 600, 700, 800, and 900 (FIGS. 5-9) for rapid recovery of donation after circulatory death (DCD) allografts in situ with extended ultra-oxygenated preservation. The methods 500, 600,700, 800, and 900 can be executed using the system shown in FIGS. 1 , 2, 3 and / or 4. For purposes of simplicity, the methods 500, 600,700, 800, and 900 are shown and described as being executed serially; however, it is to be understood and appreciated that the present disclosure is not limited by the illustrated order as some steps could occur in different orders and / or concurrently with other steps shown and described herein. Moreover, not all illustrated aspects may be required to implement the methods500, 600, 700, 800, and 900, nor are methods 500, 600, 700, 800, and 900 limited to the illustrated aspects. While a DCD donors and allografts are described herein, it should be understood that the methods(s) can be utilized with respect to other types of donors and allografts, including, but not limited to donation after brain death (DBD) donors and DBD allografts.

[0045] FIG. 5 shows a general method 500 for rapid recovery of DCD allografts in situ with extended ultra-oxygenated preservation that can be applied to any DCD allograft. Optionally, at 502 an ultra-oxygenated solution can be prepared. The ultraoxygenated solution can include, for instance, cross packed red blood cells, a perfusate such as del Nido cardioplegia, and a plurality of additives configured to improve a metabolic outlook and prevent inflammation and / or injury of the DCD allograft.Preparing the ultra-oxygenated solution can include mixing the volumes of the components (e.g., in a separate container and / or in the reservoir of the flush circuit). Additionally and / or alternatively, preparing the ultra-oxygenated solution can include oxygenating the mixed solution (e.g., with an oxygenator adding oxygen and / or adding or removing carbon dioxide from the solution). The oxygenation can occur before the solution is placed in the reservoir and / or can occur when the solution is in the reservoir (as shown in FIG. 2). The solution can be oxygenated at 100%, or in another instance at a percentage from 21% to 100% fraction of inspired oxygen. At 504, optionally the DCD donor can be surgically opened (e.g., by a sternotomy, a laparotomy, or the like) depending on the allograft and / or the previous state of the donor (e.g., already opened for a medical intervention and / or by injury). The opening can access at least a portion of the DCD allograft. If the allograft is not an internal organ, then this step may be skippable. Opening the DCD donor can additionally and / or alternatively, include steps for clamping necessary arteries and / or performing additional necessary surgical steps (e.g., venting, dissections, etc.) to prepare the donor for flushing and extraction of the allograft(s). While not shown, the pH of the ultra-oxygenated solution can also be set (e.g., to 7.50) during the mixing of components and the oxygenation.

[0046] At 506, at least one artery of a DCD allograft within the donor can be cannulated and the cannula (e.g., 114) can then be connected to the flush circuit (e.g., flush circuit 102). At 508, the DCD allograft can be flushed with the ultra-oxygenatedsolution (as described in detail above) for a time and at a pressure and / or flow rate and a temperature. The flushing can occur for an extended duration and at a pressure that mimics and / or allows for physiological perfusion (e.g., physiological coronary perfusion for the heart) to prevent endothelial damage. For instance, the time can be from 4 minutes to 30 minutes (e.g., 5 minutes, 8 minutes, 10 minutes, 15 minutes, 20 minutes, or the like, plus or minus up to 5 minutes). The flow rate can be fixed and / or variable and can be from 100 CC / min to 300 CC / min (e.g., from 100 CC / min to 250 CC / min, from 125 CC / min to 200 CC / min, from 150 CC / min to 200 CC / min, or the like). Put another way the pressure range (also referred to as root vent pressure) measured in and / or near the cannula (e.g., in the cannula and / or in the tubing of the flush circuit) can be from 40 mmHg to 120 mm Hg (e.g., from 50 mmHg to 100 mmHg, from 75 mmHg to 100 mmHg, from 90 mmHg to 110 mmHg, from 60 mmHg to 80 mmHg, from 65 mmHg to 85 mmHg, from 70 mmHg to 80 mmHg, or the like). For pediatric patients the time can be the same, the flow rate can be from 30 CC / min to 200 CC / min (depending on the age and size of the pediatric patient) with respective lowering of pressure measurements. The pressure in the cannula can be measured by a sensor and can be altered (e.g., by a pressure regulator) to maintain a preferred inflow pressure (as discussed in more detail with respect to FIG. 9).

[0047] The temperature of the solution during flushing, for both adult and pediatric patients, can be from 4°C to 12°C (plus or minus 4°C). The temperature of the allograft can also be altered to within the 4°C to 12°C temperature range using cooling and / or heating methods (e.g., saline, cooling sources, heat sources, etc.). For example, the temperature of the solution and the temperature of the allograft can be maintained, after initial lowering of temperature of the allograft, at 4°C, at 10°C, or the like (plus or minus 4°C).

[0048] At 510, the DCD allograft can be extricated from the DCD donor. For example, the extraction can be a cardiectomy (heart), a pneumonectomy (lung(s)), a hepatectomy (liver), a nephrectomy (kidney), or the like. At 512, the DCD allograft can then be transported and transplanted. The allograft can be prepared for transportation (e.g., attached to a perfusion machine, attached to a cross-circulation system, placed in a temperature-controlled carrier system (e.g., a cooler or the like), and / or the like),transported as necessary, tested for viability, and if still viable transplanted to a recipient.

[0049] FIG. 6 shows a method 600 for rapid recovery of a DCD heart in situ with extended ultra-oxygenated preservation. At 602, a sternotomy or similar procedure to open up at least the chest cavity can be performed on the donor. A sternotomy (also referred to as a median sternotomy), or the like, may not be required if the chest cavity of the donor has been previously opened (e.g., as part of medical care, because of injuries, or the like). The sternotomy can include making a vertical incision down the middle of the chest and through the sternum (e.g., using a sternal saw). A sternotomy allows access to at least the heart, lungs, and thymus. At 604, the left heart and the right heart can be vented. For example, by at least one incision in a right and / or left pulmonary vein, a right and / or left atrial appendage, through the interatrial groove, and / or an inferior vena cava. Venting can decompress the heart (e.g., remove air and / or fluid from the heart), improve surgical visibility, and / or prevent potential damage to the myocardium. At 606, an aortopulmonary window can be dissected to form a connection between the aorta and the pulmonary artery, allowing blood and / or the ultra-oxygenated solution to flow between them. At 608 the aorta can be clamped to temporarily stop blood flow to the heart through that section of the aorta to allow the ultra-oxygenated solution to be flushed through the heart. At 610, the bifurcated aortic root can be cannulated. The cannula (e.g., 114) can then be connected to the flush circuit (e.g., flush circuit 102) and at 612, the heart can be flushed with the ultra-oxygenated solution (as described in detail above) for a time and at a pressure and / or flow rate and a temperature. For instance, the time can be from 5 minutes to 20 minutes (e.g., 5 minutes, 8 minutes, 10 minutes, 15 minutes, or the like plus or minus up to 5 minutes). The flow rate can be fixed and / or variable and can be from 80 CC / min to 300 CC / min (e.g., from 100 CC / min to 250 CC / min, from 125 CC / min to 200 CC / min, from 150 CC / min to 200 CC / min, or the like. Put another way the pressure range measured in and / or near the cannula (e.g., in the cannula and / or in the tubing of the flush circuit) can be from 50 mmHg to 120 mm Hg (e.g., from 50 mmHg to 100 mmHg, from 75 mmHg to 100 mmHg, from 90 mmHg to 110 mmHg, from 60 mmHg to 80 mmHg, from 65 mmHg to 85 mmHg, from 70 mmHg to 80 mmHg, or the like). For pediatric patients the timecan be the same, the flow rate can be from 30 CC / min to 200 CC / min (depending on the age and size of the pediatric patient) with respective lowering of pressure measurements. The pressure in the cannula can be measured by a sensor and can be altered (e.g., by a pressure regulator) to maintain a preferred inflow pressure (as discussed in more detail with respect to FIG. 9). The temperature of the solution during flushing, for both adult and pediatric patients, can be from 4°C to 12°C. For example, the temperature of the solution and the temperature of the allograft can be maintained, after initial lowering of temperature of the allograft, at 4°C, at 10°C, or the like (plus or minus 4°C). The heart can then be removed (surgically), transported, and then transplanted.

[0050] FIG. 7 shows a method 700 for rapid recovery of a DCD liver and / or DCD kidney in situ with extended ultra-oxygenated preservation. At 702, a midline laparotomy, or similar procedure, can be performed to open up at least a portion of the abdominal cavity of the donor. A midline laparotomy, or the like, may not be required if the abdominal cavity of the donor has previously been opened (e.g., as part of medical care, because of injuries, or the like). In a midline laparotomy an incision can be made vertically down the middle of abdomen, along the lineal alba and extending from the near the pubis to near the umbilicus, to allow the surgical team access to the abdominal cavity. At 704, the abdominal aorta can be accessed and at 706 the supraceliac artery can be cross clamped to temporarily stop blood flow towards the liver and / or the kidney to allow the ultra-oxygenated solution to be flushed through the liver and / or the kidney. At 708, the abdominal aorta can be cannulated and the cannula can then be connected to the flush circuit (e.g., flush circuit 102). At 710, the kidney and / or the liver can be flushed with the ultra-oxygenated solution (as described in detail above) for a time and at a pressure and / or flow rate and a temperature. For instance, the time can be from 4 minutes to 30 minutes (e.g., 5 minutes, 8 minutes, 10 minutes, 15 minutes, 20 minutes, or the like plus or minus up to 5 minutes). The flow rate can be fixed and / or variable and can be from 80 CC / min to 500 CC / min (e.g., from 100 CC / min to 300 CC / min, 100 CC / min to 250 CC / min, from 125 CC / min to 200 CC / min, from 150 CC / min to 200 CC / min, or the like). Put another way the pressure range measured in and / or near the cannula (e.g., in the cannula and / or in the tubing of the flush circuit) can be from 50mmHg to 120 mm Hg (e.g., from 50 mmHg to 100 mmHg, from 75 mmHg to 100 mmHg, from 90 mmHg to 110 mmHg, from 60 mmHg to 80 mmHg, from 65 mmHg to 85 mmHg, from 70 mmHg to 80 mmHg, or the like). For pediatric patients the time can be the same, the flow rate can be from 30 CC / min to 200 CC / min (depending on the age and size of the pediatric patient) with respective lowering of pressure measurements. The pressure in the cannula can be measured by a sensor and can be altered (e.g., by a pressure regulator) to maintain a preferred inflow pressure (as discussed in more detail with respect to FIG. 9). The temperature of the solution during flushing, for both adult and pediatric patients, can be from 4°C to 12°C (plus or minus 4°C). For example, the temperature of the solution and the temperature of the allograft can be maintained, after initial lowering of temperature of the allograft, at 4°C, at 10°C, or the like (plus or minus 4°C). The liver and / or the kidney can then be removed (surgically), transported, and then transplanted.

[0051] FIG. 8 shows a method 800 for rapid recovery of at least one DCD lung in situ with extended ultra-oxygenated preservation. At 802, a sternotomy or similar procedure to open up at least the chest cavity can be performed on the donor. A sternotomy (also referred to as a median sternotomy), or the like, may not be required if the chest cavity of the donor has been previously opened (e.g., as part of medical care, because of injuries, or the like). The sternotomy can include making a vertical incision down the middle of the chest and through the sternum (e.g., using a sternal saw). A sternotomy allows access to at least the heart, lungs, and thymus. At 804, the left heart and the right heart can be vented. For example, by at least one incision in a right and / or left pulmonary vein, a right and / or left atrial appendage, interatrial groove, and / or an inferior vena cava. Venting can decompress the heart (e.g., remove air and / or fluid from the heart), improve surgical visibility, and / or prevent potential damage to the myocardium. At 806, the ascending aorta can be cross clamped to temporarily stop blood flow through that section of the aorta. At 808, a cannula (e.g., cannula 114) (e.g., a right angle cannula or the like) can be placed in the pulmonary artery relative to the pulmonic valve. The cannula can then be connected to the flush circuit (e.g., flush circuit 102) and at 810, at least one lung can be flushed with the ultra-oxygenated solution (as described in detail above) for a time and at a pressure and / or flow rate and atemperature. For instance, the time can be from 5 minutes to 20 minutes (e.g., 5 minutes, 8 minutes, 10 minutes, 15 minutes, or the like plus or minus up to 5 minutes). The flow rate can be fixed and / or variable and can be from 80 CC / min to 500 CC / min (e.g., from 100 CC / min to 300 CC / min, from 100 CC / min to 250 CC / min, from 125 CC / min to 200 CC / min, from 150 CC / min to 200 CC / min, or the like. Put another way the pressure range measured in and / or near the cannula (e.g., in the cannula and / or in the tubing of the flush circuit) can be from 50 mmHg to 120 mm Hg (e.g., from 50 mmHg to 100 mmHg, from 75 mmHg to 100 mmHg, from 90 mmHg to 110 mmHg, from 60 mmHg to 80 mmHg, from 65 mmHg to 85 mmHg, from 70 mmHg to 80 mmHg, or the like). For pediatric patients the time can be the same, the flow rate can be from 30 CC / min to 200 CC / min (depending on the age and size of the pediatric patient) with respective lowering of pressure measurements. The pressure in the cannula can be measured by a sensor and can be altered (e.g., by a pressure regulator) to maintain a preferred inflow pressure (as discussed in more detail with respect to FIG. 9). The temperature of the solution during flushing, for both adult and pediatric patients, can be from 4°C to 12°C (plus or minus 4°C). For example, the temperature of the solution and the temperature of the allograft can be maintained, after initial lowering of temperature of the allograft, at 4°C, at 10°C, or the like (plus or minus 4°C). The lung(s) can then be removed (surgically), transported, and then transplanted.

[0052] It should be understood that methods 600, 700, and 800 can be performed separately and / or in combination (e.g., overlapping, simultaneously, and / or sequentially) depending on the donor allograft viability and recipient needs. It should also be understood that that methods 600, 700, and 800 are non-limiting examples and other types of allografts can be recovered based on the above described methods.

[0053] FIG. 9, shows a method 900 for closed loop regulation of the inflow pressure of the ultra-oxygenated solution during the flushing steps described above. The method 900 can be performed by a processor (e.g., processor 304) of a controller (e.g., controller 212) in communication with at least a portion of a pressure regulation system (e.g., 108). At 902, a preferred perfusion inflow pressure can be set. The preferred perfusion inflow pressure can be, for example, from 60 mmHg to 80 mmHg. The preferred perfusion inflow pressure may depend on the DCD allograft - size, type,health information, etc. The preferred perfusion inflow pressure may alternatively be pre-set. Once the ultra-oxygenated solution has begun to be flushed through the system (e.g., 100) and through the DCD allograft the closed loop control can begin. At 904 data (e.g., pressure measurements of the inflow pressure) can be received from a pressure sensor. The pressure sensor can be positioned near the cannulation of the DCD allograft. The pressure sensor can be positioned in a separate lumen (e.g., as shown in dual lumen cannula 402 in FIG. 4) or attached to a single cannula lumen. (e.g., on an outside and / or an inside (not shown). The pressure sensor can measure the inflow pressure at a frequency and send the measurements to the processor. At 906 a difference between the pressure measurement and a desired inflow pressure of the ultra-oxygenated solution into the DCD allograft can be determined. At 908 the inflow pressure can be adjusted via a pressure regulator (e.g., pressure regulator 208) to reach the desired inflow pressure in response to the measured inflow pressure being outside a predetermined boundary (e.g., 1 mmHg different, 2 mmHg different, 5 mmHg different, or the like). The flow regulator(s) can be, for example pinch valves that can be at least partially opened and / or closed by a controller to alter the flow rate of the ultraoxygenated solution. The cycle can continue until the volume of the ultra-oxygenated solution has been emptied (e.g., into the DCD allograft).V. Example REUP System Implementation

[0054] FIG. 10 shows an example of a system that can be used in practice to implement the rapid recovery of donor allog raft(s) with extended ultra-oxygenated preservation (REUP) (referred to herein as a REUP system and / or a REUP device). It should be understood that this is only one example for illustrative purposes and should not be considered limiting. The REUP system can simplify the transplant donor procurement process, particularly with DCD donors; provide a standardized and reproducible approach to donor allograft perfusion; improve perfusion quality; optimize preservation technique; provide real-time quality assessment of the donor profusion process, including metabolic assessment through biochemical analysis; save significant costs compared to normothermic regional perfusion (NRP) and ex-vivo machine perfusion; utilize minimal electrical power (e.g., battery supplied or the like); and canavoid the detrimental double hit ischemic reperfusion injury / cycle that occur in NRP and ex-vivo machine perfusion.

[0055] The REUP system shown in FIG. 10 can be used in the removal of a donor heart from a donor and extended ultra-oxygenated preservation of the donor heart. The REUP system can be designed to preserve human organs donated for transplantation. The REUP system can utilize an organ specific preservation solution and can deliver the solution in a controlled fashion (e.g., the REUP system can include one or more biologic readouts to ensure consistent outcomes). The REUP system can oxygenate the solution (as shown in FIG. 12, element B) or the solution can be pre-oxygenated.

[0056] The REUP system can include both disposable and reusable components. The disposable components can include a perfusion cannula with pressure readout line, a solution bag, a pressure chamber (also referred to as a pressure bag), an infusion tubing, a pinch valve, one or more sensors, and optionally, a biomarker read out line. The pressure chamber may also incorporate one or more cooling / insulation elements to maintain the solution within a specified temperature range. The controller for pressure regulation and biomarker readout, including a pH monitor, can be reusable and can have wired and / or wireless connectivity (e.g., BLUETOOTH) with sensors in the read out tube(s).

[0057] The REUP system can be used by at least an organ preservationist, a procurement surgeon, or the like (e.g., another member of the procuring team). The organ preservationist can coordinate one or more aspects of organ procurement (e.g., in time) and can prepare the REUP system and oxygenated solution prior to organ procurement. The organ preservationist can hand the procurement surgeon the profusion tubing, pressure readout line, and the biomarker read out line in a sterile fashion. As an example, the tubing can be connected to the organ preservation solution bag, and the pressure readout and biomarker readout lines can be connected to the pressure controller and biomarker readout device. The organ preservationist can adjust the pressure setting to a preferred level for the surgery. The organ procurement surgeon can cannulate the donor allograft (e.g., in the allograft’s vascular inflow vessels) using the dual lumen cannula. The surgeon can connect the perfusion line (infusion tubing) and pressure readout line (pressure tubing for readout) to the duallumen cannula in a sterile fashion after the dual lumen cannula is secured. Once the procuring surgeon determines that the dual lumen cannula and lines (infusion tubing and pressure tubing) are secure, organ perfusion will commence. After completion of the organ perfusion, the procurement surgeon can explant the donor organ, and the organ will be stored (e.g., the storage can be in accordance with the procuring team’s preference).

[0058] FIG. 11 shows photographs of the solution bag and the pressure bag (also referred to as the pressure chamber). As noted, prior to the preservation of the allograft, the perfusion solution can be prepared and placed in a solution bag. The solution bag can then be positioned within the pressure bag. During preservation, the perfusion flow can be driven by pressure applied to the solution bag via the pressure bag and in accordance with the controllable flow regulators. A mechanical pump can also be used. The perfusion flow can then be directed (e.g., by associated tubing and cannulae) into as the aorta for a heart, at least one organ artery for other organs, and can also be directed into the portal vein for liver grafts specifically. The pressure chamber can also include cooling pads or another temperature control mechanism (e.g., eutectic cooling units, or the like) that can maintain the temperature of the solution stably within a desired range.

[0059] The solution can be injected into the solution bag, as shown in FIG. 12, element A. Any additives can be mixed with the base preservation solution and the composition of the solution can be checked by taking a sample from the solution bag to confirm metabolic status. Additives and / or solution can be added as required and tailored for specific organs to reach the desired composition. Prior to the preservation of the organ, the perfusate also can be oxygenated using a sterile disposable circuit containing an oxygenator and stored in plastic sterile bags (e.g., the solution bags). The oxygenator circuit is shown in FIG. 12, element B. The oxygen can be supplied from an oxygen supply to an oxygenator (a gas exchange / transfer device that the preservation solution passes through to be oxygenated). The oxygenator can inject the desired quantity of oxygen into the non-oxygenated solution to create an oxygenated preservation solution, used by the REUP system and in the RELIP methods. The solution bags can be designed to permit passive (e.g., gravity fed) flow through anoxygenator to another solution bag and / or can be actively flowed through the oxygenator with an additional pump (not shown).

[0060] Referring back to FIG. 10, the duel lumen cannula can be inserted into at least an aorta or artery of an allograft (depending on the type of allograft) to connect the infusion tubing to flow the solution from the solution bag to the allograft. One lumen can allow for easy flow of preservation solution and the other lumen can be dedicated to accurate pressure readouts (e.g., from a pressure sensor) in the vessel being perfused (FIG. 13 shows two views of an example dual lumen cannula). The effluent read out including the effluent probe monitor (e.g., chemical sensor(s), temperature sensor(s), or pH sensor, or the like) can separately be inserted into at least a portion of the allograft to collect biomarker readouts in the organ’s primary vascular drainage. The controller can be in communication (wired as shown (via the read out lines) and / or wireless) with at least the pressure sensor(s) and the sensor(s) of the effluent probe monitor. The controller can also be in communication with the pinch valve to automatically change the perfusion pressure of the donor organ if the pressure is above or below a pre-set pressure range (e.g., 60 mmHg - 80 mmHg, or the like). Example views of a pinch valve are shown in FIG. 14. The pinch valve can be a mechanical pinch valve that can be positioned at least partially on the infusion tubing. The controller can also provide a biochemical analysis of the effluent from the donor organ (e.g., pH, metabolic chemical compositions, or the like) that can indicate organ preservation status.VI. Case Studies

[0061] The following case studies demonstrate the viability of using Rapid-recovery with extended ultra-oxygenated preservations (REUP) to recover a donation after circulatory death (DCD) heart for successful transplant in a living recipient.

[0062] Case Study 1

[0063] This case reports a method for the recovery of hearts for transplantation from deceased donors after circulatory death that obviates the need for thoracoabdominal normothermic regional perfusion or ex situ perfusion systems. The technique used herein involves the use of a flush circuit to oxygenate 2 liters of a cold preservation solution comprising packed red cells, del Nido cardioplegia, and otheradditives. The solution is administered at a mean aortic-root pressure of 80 mm Hg over a period of approximately 10 to 12 minutes. This technique has been named rapid recovery with extended ultra oxygenated preservation (REUP). The REUP technique and the early outcomes in the first three recipients of hearts recovered using this method are described below.

[0064] Recipient and Donor 1

[0065] A 40-year-old man with advanced nonischemic cardiomyopathy and heart failure caused by sarcoidosis and with end-stage renal disease caused by hypertension and diabetes mellitus was listed for dual heart and kidney transplantation. An echocardiogram revealed a left ventricular ejection fraction of 25%, a pulmonary vascular resistance (PVR) of 2.2 Woods units (normal value, 0 to 2.0), a cardiac index of 1.8 liters per minute per square meter of body-surface area (normal, 2.4 to 4.0), and a maximal oxygen consumption of 8.9 ml per kilogram of body weight per minute (normal, 27 to 50). The donor was a 16-year-old boy who had sustained gunshot wounds to the anterior neck and had permanent loss of neurologic function. An echocardiogram showed a structurally normal heart with normal biventricular function and a predicted heart mass (a ratio that conveys the appropriate donor-to-recipient size match in heart transplantation) of 0.84. The normally accepted range of predicted heart mass is between 0.8 and 1.2, but excellent outcomes have been reported in patients when the predicted heart mass is outside this range

[0066] Recipient and Donor 2

[0067] A 60-year-old man with nonischemic cardiomyopathy, heart failure, and recurrent ventricular arrhythmias despite medical management and several catheter ablations for his arrhythmias was listed for heart transplantation. An echocardiogram revealed a left ventricular ejection fraction of 25%, a PVR of 1.3 Woods units, and a cardiac index of 2.0 liters per minute per square meter. The donor was a 31 -year-old man who had had a drug overdose, had received 20 minutes of cardiopulmonary resuscitation, and had permanent loss of neurologic function. The echocardiogram revealed normal biventricular function and structurally normal valves. The predicted heart mass was 0.76.

[0068] Recipient and Donor 3

[0069] A 56-year-old man with ischemic cardiomyopathy and chronic kidney disease (stage 4) underwent placement of a Heartmate III (Abbott) left ventricular assist device in 2019 as a bridge to transplantation. He was listed for heart and kidney transplantation. An echocardiogram revealed a left ventricular ejection fraction of 5 to 10%, mildly reduced right heart function, and a PVR of 1.6 Woods units. The donor was a 25-year-old man who had sustained a gunshot wound to the head and had undergone external ventricular drain placement, with subsequent permanent loss of neurologic function. An echocardiogram revealed normal biventricular function and valves. The predicted heart mass was 0.93

[0070] Organ Recovery

[0071] Before withdrawing life-sustaining care, a flush circuit was constructed consisting of a standard normothermic regional perfusion circuit along with an additional reservoir and a heater and cooler. The extracorporeal circuit was primed with a solution including 2 units of crossed packed red cells, 2 liters of del Nido cardioplegia solution, and additional components. After the components were mixed, the preservation solution was oxygenated through the extracorporeal circuit and sweep gas at a rate of 2 liters per minute and 100% fraction of inspired oxygen (FiO2) was maintained for 5 minutes. Samples were drawn to test arterial blood gases, and bicarbonate was added as needed to target a pH level of 7.5, bicarbonate level of 30 mmol per liter, and a partial pressure of oxygen above 500 mm Hg. The heater and cooler ensured a flush temperature of 4°C.

[0072] A final declaration of death in the context of DCD was made after a 5-minute standoff period. A sternotomy was performed, and the left and right heart were vented with incisions in the right pulmonary veins or the interatrial groove and in the inferior vena cava. A cross-clamp was placed across the ascending aorta in the same manner as during a standard procurement, which eliminates any possibility of systemic or brain perfusion. A bifurcated aortic-root cardioplegia needle was placed proximal to the crossclamp, and the root was manually de-aerated. A flush line was placed on one limb of the root needle, and a pressure line was placed on the other. 2 liters of the extended oxygenated flush was delivered through the aortic-root needle at a mean pressure of 80 mmHg. This correlated to a flow of approximately 200 ml per minute and thus requiredapproximately 10 to 12 minutes to complete. During the flush, 10°C saline was placed on the heart. A donor cardiectomy was then performed in standard fashion, and the heart was placed in a 10°C cooler for transport. There were no cases in which this technique was attempted and the donor heart was subsequently discarded. The time from the first declaration of death to flush ranged from 8 to 10 minutes.

[0073] Heart Transplantations

[0074] Recipients underwent sternotomy with central aortic and bicaval venous cannulation. After cardiopulmonary bypass was initiated, recipient cardiectomy was performed. The donor heart was inspected for normal valve structures. The donor heart anastomoses were then performed in the following order: left atrium, inferior vena cava, pulmonary artery, and aorta. After the aorta was anastomosed, the aortic cross-clamp was removed, and the superior vena cava anastomosis was performed while the heart was being reperfused. After reperfusion, patients were weaned from cardiopulmonary bypass. Intraoperative echocardiography revealed normal biventricular function in recipients 1 and 2 and normal left ventricular and mildly depressed right ventricular function in recipient 3. Epicardial pacing wires and mediastinal and pleural chest tubes were placed, and the chests were closed.

[0075] Postoperative Outcomes

[0076] Postoperatively, all three recipients recovered well and had uncomplicated stays in the intensive care unit. The cardiac index in the recipients ranged from 2.8 to 4.4 liters per minute per square meter during the first postoperative week, and all three were weaned from ionotropic drips by day 7 after transplantation. Follow-up postoperative echocardiography revealed normal biventricular function. Recipient 1 received temporary continuous renal replacement therapy followed by intermittent hemodialysis but later had full renal recovery. All the patients received a standard immunosuppression regimen that included prednisone, mycophenolate mofetil, and tacrolimus. The recipients underwent postoperative serial echocardiography and right heart catheterizations with biopsy. They continued to have normal biventricular function and no evidence of acute cellular or antibody mediated rejection as of 6 months after heart transplantation.

[0077] Case Study 2

[0078] Here, the rapid recovery with extended ultra oxygenation preservation (REUP) technique is highlighted combined with 10C static cold storage to recover an older donor allograft (45 years of age) with a prolonged 8-hour ischemic time (477 minutes). The recipient underwent successful heart transplantation with subsequent normal biventricular function and excellent postoperative outcomes out to 8 months following surgery.

[0079] A 61 -year-old male with ischemic cardiomyopathy secondary to coronary artery disease status post multiple percutaneous coronary interventions developed cardiogenic shock requiring inpatient admission with inotropic support. He underwent Heartmate III (Abbott) left ventricular assist device (LVAD) placement in 2024 as a bridge to transplantation. Nine months after LVAD placement, he received an offer for heart transplantation. He was listed as status 3 as he developed persistent episodes of significant gastrointestinal bleeding secondary to his anticoagulation for his LVAD. He had several recent hospitalizations prior to transplant but was not admitted at the time of receiving his heart offer. The donor was a 45-year-old male with anoxic brain injury. The donor heart had a normal echocardiogram. The predicted heart mass ratio was 0.90. Before withdrawal of life-sustaining care, a modified NRP flush circuit with reservoir was constructed. The components of the preservation solution included 2 units of packed red blood cells (pRBCS), 2 liters of del Nido cardioplegia solution, and other components. After mixing the components, the circuit was started at 2 liters per minute and the perfusate was oxygenated. A pH of 7.5 and partial pressure of oxygen of 500 mm Hg was targeted. Arterial blood gases were analyzed serially until temperature-correct values were achieved.

[0080] Initial declaration of death was made 15 minutes after withdrawal, followed by the final declaration of death after a 5-minute wait period. A sternotomy was performed, the left and right heart were vented, and an ascending cross clamp was placed. A bifurcated ascending root vent was used to administer the perfusate with an aortic root pressure of 80 mm Hg and a flow rate of 200 cc / minute. The donor cardiectomy was performed in standard fashion and the heart was placed in the 10C cooler. The time from withdrawal to flush was 22 minutes, while the asystolic warm ischemic time was 7 minutes.

[0081] The recipient underwent re-do sternotomy with central aortic and bicaval venous cannulation. After cardiopulmonary bypass was initiated, recipient cardiectomy and LVAD explanation were performed. The heart was implanted in standard fashion. After reperfusion for 60 minutes, cardiopulmonary bypass was weaned. Dopamine was used for inotropic support. Intraoperative echocardiography revealed normal biventricular function with normal valves.

[0082] The total ischemic time was 477 minutes. This consisted of 30 minutes for initiation of flush, donor cardiectomy, and heart storage, 30-minute ground time from donor hospital to airport, 330 minutes for air travel, 30-minute ground time from airport to recipient hospital, and 57 minutes for completion of recipient cardiectomy with LVAD explantation coupled with heart implantation.

[0083] Postoperatively, the recipient recovered well with an uncomplicated hospital stay. His cardiac index ranged from 2.6 to 3.9 L / min / m2 during the first 5 days. His dopamine was weaned by postoperative day (POD) 6, and he was discharged on POD18. His follow up echocardiograms revealed normal biventricular function with structurally normal valves. His right heart catheterization (RHC) and biopsy 4 months following transplantation demonstrated normal filling pressures and cardiac index with mild acute cellular rejection (1 R) and no antibody mediated rejection. After a short course of steroids, his follow-up RHC and biopsy at 6 months revealed normal filling pressure and cardiac index with no acute cellular or antibody-mediated rejection. The recipient is doing well more than 8 months post heart transplantation.

[0084] Case Study 3

[0085] This case highlights how the innovative RELIP technique enabled the successful transplant of a donation after circulatory death (DCD) heart without preimplant reanimation despite prolonged exposure to circulatory arrest before preservation. This approach facilitated successful adult heart transplantation in the setting of a “no-touch” period of 37 minutes of circulatory arrest, comprising 14 minutes of pulseless electrical activity (PEA) warm ischemic time (WIT) plus 23 minutes of asystolic WIT (AWIT) with a total ischemic time of 5 hours.

[0086] A 58-year-old male with non-ischemic cardiomyopathy developed cardiogenic shock requiring inpatient admission with inotropic support. At the time ofinitial presentation, he was not a candidate for transplantation due to active tobacco and cannabis use. He therefore underwent Heartmate III (Abbott) left ventricular assist device (LVAD) placement in 2024 as a bridge to transplant. After seven months without substance use, he was listed as status 4 and received a DCD organ offer. The donor was a 32-year-old male with anoxic brain injury secondary to cardiac arrest of unknown etiology. The donor heart had a normal transthoracic echocardiogram. The predicted heart mass ratio was 0.76. The left heart catheterization was normal.

[0087] Before the withdrawal of life-sustaining care, a modified NRP flush circuit with reservoir was constructed as described previously. The preservation solution included 2 units of packed red blood cells (pRBCs), 2 liters of del Nido cardioplegia solution, and other components. After mixing the components, the perfusate was oxygenated. A pH of 7.5 and partial pressure of oxygen of 400-500 mm Hg were targeted.

[0088] The donor withdrawal location was in the intensive care unit far away from the operating theatre. After withdrawal of life sustaining care, the patient became agonal as defined by a systolic blood pressure of <50mm Hg after 5 minutes. The patient then converted to and remained in PEA for 14 minutes, and subsequently initial declaration of circulatory death was made at the onset of asystole. After 5 minutes in asystole, final declaration was made. The patient was then transported to the operating room, which resulted in a prolonged transport time due to distant location. More than twenty minutes following asystole, a sternotomy was performed, the left and right heart were vented, and an ascending cross clamp was placed. A bifurcated ascending root vent was used to administer the perfusate with an aortic root pressure of 80 mm Hg. The donor cardiectomy was performed in standard fashion and the heart was placed in 10°C static cold storage. The total time from skin incision to the initiation of perfusate flush was 2 minutes.

[0089] The recipient underwent re-do sternotomy with central aortic and bicaval venous cannulation. After cardiopulmonary bypass was initiated, recipient cardiectomy and LVAD explanation were performed. The heart was implanted in standard fashion. After reperfusion for 45 minutes, cardiopulmonary bypass was successfully weaned with the use of dopamine and dobutamine for inotropic support. Intraoperativeechocardiography revealed normal biventricular function with normal valves. Overall, the time from withdrawal to flush was 42 minutes with a functional WIT (FWIT) of 42 minutes, encompassing a total of 37 minutes of circulatory arrest with 14 minutes of PEA followed by 23 minutes of AWIT.

[0090] Postoperatively, the recipient continued to have normal allograft function and recovered well with an uncomplicated hospital stay. His cardiac index ranged from 2.8 to 4.0 L / min / m2during the first 5 days. His inotropes were weaned completely off by postoperative day POD6. His follow up echocardiograms revealed normal biventricular function with structurally normal valves. Surveillance right heart catheterization (RHC) and biopsy revealed no evidence of rejection. The recipient’s remaining postoperative course was uncomplicated, and he continued to do well, for more than 30 days out from transplantation.

[0091] This case highlights the capability of the novel REUP technique for the successful recovery and transplant of a DCD heart without pre-implant reanimation after a prolonged “no-touch” period including 14 minutes of PEA and 23 minutes of AWIT. Although prior concerns have been posed regarding the utilization of the REUP technique in the setting of prolonged “no-touch” periods, this case underscores the promise of REUP in these scenarios — highlighting its broad applicability and potential for worldwide implications for DCD hearts, even in the setting of prolonged PEA and AWIT.

[0092] Cardiac allografts from DCD donors have been used in adult heart transplantation with excellent early and midterm outcomes comparable to those from donation after brain death. Thoracoabdominal normothermic regional perfusion (TA-NRP) and direct procurement and perfusion (DPP) with commercial ex situ platforms have shown success in countries with short asystolic “no-touch” periods (5 minutes or less) including the United States, England, and Australia. However, countries such as Italy have some of the longest known “no-touch” periods, requiring up to 20 minutes of asystole prior to final declaration of death. These prolonged periods of circulatory arrest have been considered major barriers to the uptake of DCD adult heart transplant in these settings. Early studies demonstrated a 10% 30-day mortality rate and a 25% severe primary graft dysfunction (PGD) rate, and larger follow-up studies showedsimilar results. Compared to the United States, where “no-touch” periods are typically shorter, the rates of mortality and severe PGD remain significantly higher.

[0093] In these settings with prolonged 20-minute “no-touch” periods, controversy persists regarding DCD recovery technique selection and outcomes. Some hold the view that TA-NRP may be the only viable strategy in countries like Italy where a prolonged “no-touch” asystolic period is routinely observed. However, experience has demonstrated that prolonged AWIT over 10 minutes is associated with increased mortality and severe PGD following TA-NRP use during DCD heart recovery. In most reports from the Italian literature, the AWIT time ranges from 23-28 minutes with functional WIT ranging from 36-43 minutes. Here, the recipient underwent successful adult heart transplantation even in the setting of a prolonged AWIT of 23 minutes with a superseding PEA time of 14 minutes with a total FWIT of 42 minutes. Without wishing to be bound by theory it is believed that the longest reported successful DCD heart recovery involved an AWIT of 34 minutes and utilized TA-NRP for donor heart reanimation before transplantation. The case reported here outlines the successful transplantation of a DCD allograft exposed to a total time of 37 minutes of circulatory arrest prior to initiation of the REUP flush and without pre-implant reanimation. As PEA has been recognized as a form of circulatory arrest, this may be regarded as the longest case of DCD heart recovery with subsequent successful adult transplant.

[0094] The REUP technique also highlights there may not be a need for donor heart reanimation, even in the setting of prolong “no-touch” periods. In fact, it is postulated there may be a deleterious impact introduced by the additional arrest of the DCD donor heart that is necessarily introduced by reanimation techniques. Namely, that the “second hit” of cardiac arrest imposed on the donor heart following reanimation creates additional insult and non-physiologic consequence to the allograft that may impact its function after implantation. Early experiences with REUP have shown that donor heart reanimation may not be required if the pre-donation echocardiography is without concern. Ultimately, the REUP technique may help afford more patients access to DCD heart transplantation and will be appealing to international heart transplant centers with prolonged “no-touch” periods and without the need for donor heart reanimation.

[0095] From the above description, those skilled in the art will perceive improvements, changes, and modifications. Such improvements, changes and modifications are within the skill of one in the art and are intended to be covered by the appended claims.

Claims

The following is claimed:

1. A method for rapid recovery of a donation after circulatory death (DCD) allograft from a DCD donor, the method comprising:cannulating at least one artery of the DCD allograft within the DCD donor; flushing an ultra-oxygenated solution through the DCD allograft at a pressure for a time with a system comprising a flush circuit; andextricating the DCD allograft from the DCD donor for transplantation, wherein the DCD allograft is resuscitated without reanimation of the DCD allograft or systemic circulation of the donor.

2. The method of claim 1 , further comprising preparing the ultra-oxygenated solution by:preparing a solution configured to improve a metabolic outlook and prevent inflammation and / or injury of the DCD allograft, the solution comprising cross packed red blood cells and del Nido cardioplegia;oxygenating the solution from 21% to 100% fraction of inspired oxygen (FIO2) for a time; andsetting the ultra-oxygenated solution to a pH.

3. The method of claim 1 wherein the DCD allograft comprises a heart andthe cannulating the at least one artery of the DCD allograft within the DCD donor comprises positioning a cardioplegia needle into a bifurcated aortic root;the flushing the ultra-oxygenated solution through the DCD allograft at a pressure for a time comprises flushing a volume of an oxygenated perfusate solution through the aortic root needle at a flow rate of 200 cc / min for 10 minutes; andthe extricating the DCD allograft from the DCD donor for transplantation further comprises performing a cardiectomy on the DCD donor.

4. The method of claim 1 , further comprising surgically opening the DCD donor to access at least a portion of the DCD allograft.

5. The method of claim 4, wherein the DCD allograft comprises a heart and the surgically opening the DCD donor further comprises:performing a sternotomyventing left heart and right heart via incisions in a right pulmonary vein, a left atrial appendage, and / or an inferior vena cava;dissecting an aortopulmonary window; andcross clamping an aorta of the heart.

6. The method of claim 1 , wherein the time of the flushing is an extended duration and the pressure is a pressure that allows for physiologic coronary prefusion to prevent endothelial damage.

7. The method of claim 1 , further comprisingtransporting the DCD allograft with a temperature-controlled carrier system; and transplanting the DCD allograft into a recipient.

8. The method of claim 7, further comprising maintaining the DCD allograft at a temperature prior to the transplanting into the recipient.

9. The method of claim 1 , further comprising:regulating an inflow pressure of the ultra-oxygenated solution being flushed into the DCD allograft.

10. The method of claim 9, further comprising:receiving, by a system comprising a processor, a measurement of the inflow pressure of the ultra-oxygenated solution into the DCD allograft from a sensor positioned in a cannula of the flush circuit connected to the DCD allograft;determining, by the system, a difference between the pressure measurement and a desired inflow pressure of the ultra-oxygenated solution into the DCD allograft; andadjusting, by the system, the inflow pressure via a pressure regulator in communication with the processor to reach the desired inflow pressure.

11. A portable system for rapid recovery with extended ultra-oxygenated preservation of a donation after circulatory death (DCD) allograft, the system comprising:a flush circuit configured to flush an ultra-oxygenated solution through a DCD allograft to preserve the DCD allograft for transplantation, the flush circuit comprising:a reservoir configured to hold the ultra-oxygenated solution, tubing configured to connect the reservoir to the DCD allograft;a temperature control device configured to maintain the ultra-oxygenated solution at a temperature, anda pressure regulation system configured to flow the ultra-oxygenated solution into the DCD allograft at and / or near a pressure; andat least one cannula configured to be positioned in an artery of the DCD allograft to connect the tubing of the flush circuit with the DCD allograft for administration of the ultra-oxygenated solution to the DCD allograft, wherein the DCD allograft is within the donor during use of the system.

12. The system of claim 11 , further comprising an oxygenator configured to oxygenate the ultra-oxygenated solution.

13. The system of claim 11 , wherein the oxygenator oxygenates the solution from 21% to 100% fraction of inspired oxygen (FIO2) for a time.

14. The system of claim 11 , wherein the pressure regulation system comprises: a pressure sensor configured to measure a pressure of the ultra-oxygenated solution at a location in the flush circuit; anda flow regulator configured to regulate a flow rate of the ultra-oxygenated solution to the DCD allograft.

15. The system of claim 14, wherein the flow regulator is a pinch valve configured to alter the flow rate in response to the measured pressure being outside a predetermined boundary.

16. The system of claim 14, wherein the system further comprises a controller in communication with the pressure regulation system, the controller comprising:a non-transitory memory storing instructions to set and regulate inflow pressure of the ultra-oxygenated solution to the DCD allograft, anda processor configured to execute the instructions to set and regulate the inflow pressure of the ultra-oxygenated solution to the DCD allograft.

17. The system of claim 14, wherein the at least one cannula is a dual lumen cannula comprising:a perfusate infusion lumen configured to provide the ultra-oxygenated solution to the DCD allograft; anda pressure read out lumen configured to house the at least one sensor to measure the pressure of the ultra-oxygenated solution in the perfusate infusion lumen.

18. The system of claim 11 , wherein DCD allograft is a heart and the cannula is configured to be positioned in an aortic root.

19. The system of claim 18, wherein the system is configured to flush at least one liter of the ultra-oxygenated solution through the aortic root needle at a variable flow rate from 120 CC / minute to 250 CC / minute for a time from 5 minutes to 15 minutes.

20. The system of claim 11 , wherein the system is configured to provide the ultraoxygenated solution to the DCD allograft for resuscitation without reanimation of the DCD allograft or systemic circulation of the donor.

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