Repaired organ and method for making the same   

Abstract: A repaired ex vivo organ suitable for transplantation in a human, said repaired ex vivo organ having undergone ex vivo organ perfusion for a maintenance period, wherein said organ had been assessed as being unsuitable for transplantation into a human before the maintenance period and was determined to be suitable for transplantation after the maintenance period.

This application claims priority from U.S. Provisional Application No. 61/499,983, filed Jun. 22, 2011, the contents of which are incorporated herein by reference.

This invention relates to systems, processes, and methods for ex vivo organ preservation, maintenance, repair, and/or assessment. This invention also relates to preserved, maintained, repaired and/or assessed organs provided by the systems, processes and methods described herein.

Organ transplantation is lifesaving for patients. For example, lung transplants can be lifesaving for individuals with end-stage lung diseases; however, the number of patients waiting for lung transplants greatly exceeds the number of available donors. On average, 15% of lungs from multi-organ donors are used for transplantation and the rest are typically considered unsuitable.

Currently, the use of static hypothermia is widely accepted for preserving organs after removal. There are drawbacks to this method, however, such as drawbacks related to keeping an organ in a hypothermic state for a period of time. For example, the inhibition of cellular metabolism as a result of hypothermia can make it difficult to repair an organ or assess its suitability or condition during the preservation period.

In addition, many organs are considered injured or too “high risk” to be transplanted in a human. For example, more than 80% of donor lungs are considered too high risk for reasons including lung injury that typically occurs after brain death and/or complications associated with treatment in intensive care units.

Although non-optimal donor organs, such as lungs with suboptimal gas-exchange function or infiltrates visible on chest radiographs, have been used with success, increased primary graft dysfunction (an acute lung injury typically occurring within 72 hours after transplantation) has been reported in some studies. These injuries can affect early outcomes and can be associated with an increased risk of chronic graft dysfunction.

The techniques currently used to assess an organ for transplant suitability cannot adequately identify every suitable organ because of hypothermic preservation conditions and time constraints. As a result, clinicians tend to be highly conservative when selecting donors, and because of the relatively small number of organs that are deemed to be acceptable, mortality in patients awaiting transplantation is high. Furthermore, current preservation and maintenance procedures do not allow for the possibility of repairing and/or improving a suitable or high risk organ.

Having an increased number of suitable organs, such as lungs, available to transplant is a promising means of augmenting the number of organ transplants and thereby saving more lives. Accordingly, there is a desire for a system that will adequately preserve and maintain an organ for a period of time and in such a condition that it can be assessed, repaired, and/or improved in order to give the transplant recipient the best chance for recovery.

SUMMARY

An aspect of the present invention is a repaired ex vivo organ suitable for transplantation in a human, said repaired ex vivo organ having undergone ex vivo organ perfusion for a maintenance period, wherein said organ had been assessed as being unsuitable for transplantation into a human before the maintenance period and was determined to be suitable for transplantation after the maintenance period. The repaired ex vivo organ can be a lung having a best ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of more than 350 mm Hg. In some embodiments, the lung may have been assessed as being unsuitable for transplantation because its best ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen was less than 300 mm Hg. The maintenance period of time can be at least 24 hours, 8 hours, 3 hours, or 1 hour.

In some embodiments, the repaired ex vivo organ can also undergone ex vivo perfusion for a treatment period. According to some embodiments, the repaired ex vivo organ is a lung and may have been assessed as being unsuitable for transplantation because it had pulmonary edema, pneumonia, or inflammation. In embodiments where the organ is a lung and was assessed as having injury or pulmonary edema, it may have been subjected to antibiotics, hyper-perfusion techniques, beta-agonists, anti-inflammatory agents, or flow techniques during the treatment period. In embodiments where the lung was assessed as having pneumonia, it may have been subjected to antibiotics or steroids during the treatment period. In embodiments where the lung was assessed as having inflammation, it may have been subjected to gene therapy, stem cells, or anti-coagulants during the treatment period. In some embodiments, the repaired ex vivo organ can be a lung, liver, heart, kidney, or pancreas.

Another aspect of the invention is a donor organ system for repairing and/or improving a donor organ so that the donor organ is suitable for transplantation into a human. The donor organ system comprises the steps of (i) determining the status of the organ by evaluating pre-selected criteria; (ii) subjecting the organ to an acellular perfusate at normothermic temperatures for a maintenance period; and (iii) determining improvement and/or repair of the organ by re-evaluating the pre-selected criteria. In some embodiments, the maintenance period can within the range of 1 to 10 hours, 1 to 7 hours, or 1 to 3 hours. In some embodiments, step (i) can be performed concurrently with step (ii). In some embodiments, the organ can be a lung, liver, heart, kidney, or pancreas.

The donor organ system of the present invention can further comprise the step of treating the organ with a suitable medical treatment for a treatment period after step (ii). In some embodiments, the treatment period is within the range of 1 to 10 hours, 1 to 7 hours, or 1 to 3 hours.

Another aspect of the invention is a method of improving an ex vivo organ, the method comprising the steps of (i) determining the status of the organ by evaluating pre-selected criteria; (ii) subjecting the organ to an acellular perfusate at normothermic temperatures for a maintenance period; and (iii) determining improvement of the organ by re-evaluating the pre-selected criteria. In some embodiments of the invention, the organ can be a lung, liver, heart, kidney, or pancreas. In an embodiment where the organ is a lung, the pre-selected criteria can include the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen. In some embodiments the preselected criteria can show an improvement of at least 10%, at least 20%, or at least 40% between steps (i) and (iii).

For a better understanding of embodiments of the organs, processes, systems, and methods described herein, and to show more clearly how they may be carried into effect, reference will be made by way of example to the accompanying drawings in which:

FIG. 1 is a representation of the donor organ systematic process according to an embodiment of the present invention;

FIG. 2 is a schematic drawing of the ex vivo organ perfusion system according to an embodiment of the present invention;

FIGS. 3A, 3B, 3C, and 3D are graphs showing ex vivo lung function according to an embodiment of the present invention;

FIG. 4 is a representation of the process of selecting lungs for ex vivo lung perfusion according to an embodiment of the present invention;

FIG. 5 is a chart showing preservation times of lungs subjected to ex vivo lung perfusion according to an embodiment of the present invention; and

FIGS. 6 A, B, C, and D are graphs showing lung function of lungs subjected to ex vivo lung perfusion according to an embodiment of the present invention.

It will be appreciated that for simplicity and clarity of illustration, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements or steps. In addition, numerous specific details are set forth in order to provide a thorough understanding of the embodiments described herein. However, it will be understood by those of ordinary skill in the art that the embodiments described herein may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the embodiments described herein. Furthermore, this description is not to be considered as limiting the scope of the embodiments described herein in any way, but rather as merely describing the implementation of the various embodiments described herein.

The present invention generally provides a systematic process for preserving, maintaining, repairing, and/or improving an organ isolated from a donor. The process also provides a method for assessing the organ to determine whether it is suitable for transplantation into a human. Organs subjected to this process can be improved candidates for transplantation compared to organs subjected to current transplantation protocols.

The improved process of providing an organ suitable for transplantation into a human is set out in FIG. 1 as process 100. Process 100 begins with donor organ 102. Donor organ 102 has been isolated from the donor by suitable procedures and is considered to be an ex vivo organ. Organs suitable for the present invention include any organ suitable for transplantation, including one or both lungs, liver, heart, kidney, pancreas, or a composite tissue, such as a face or hand. One or both lungs are preferred. Once donor organ 102 has been isolated from the donor, it can be subjected to standard evaluation 104. Standard evaluation 104 methods include methods traditionally used by the skilled person to assess whether an organ is suitable for transplantation. For example, clinicians often assess suitability based on factors such as the rate of change of the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen (PO2 or PaO2/FIO2), pulmonary vascular resistance, peak inspiratory pressure, or dynamic compliance, bronchoscope findings, radiologic assessment, and direct examination of the lung during procurement. In addition, lungs that are obtained from donors without a heartbeat are often not considered suitable for transplantation as their function is more unpredictable.

If donor organ 102 is deemed to be an injured organ 108 by standard evaluation 104, it will be categorized according to treatment protocols. An injured organ is one that is deemed sub-optimal or too high risk to be successfully transplanted into a human. For example, an injured organ may have be indicated as such because of the presence of pneumonia, edema, or inflammation. Also, the injured organ may have an injury such as a disruption of the blood-alveolar barrier, a severe injury, such as a mechanical injury, or an injury that is difficult to determine, such as a non-specific injury. In addition, or in other cases, the injured organ may have sub-optimal physiologic criteria, such as sub-optimal PaO2/FIO2, pulmonary vascular resistance, peak inspiratory pressure, or dynamic compliance. Categorization of injured organ 108 can occur as part of standard evaluation 104, or as a separate step once donor organ 102 has been determined to be an injured organ 108. Categories of injury of injured organ 108 include, but are not limited to, severe injury 112, pneumonia 114, edema 116, inflammation 118, and non-specific injury 120. Generally, any organ that is considered “high risk” for transplantation into a human can fall under a category of injury.

Each injured organ 108 can be treated, with the intent to repair, according to the category of injury it falls. It will be recognized by the skilled person that injured organ 108 may fall under more than one category and may therefore benefit from a mixture of treatments. Ideally, every injured organ 108 can undergo ex vivo organ perfusion (sometimes referred to as “EVOP”) before or concurrently with treatment. An ex vivo perfusion system is described further below.

Treatment of injured organ 108 can involve any suitable treatment. For example, if injured organ 108 falls under category severe injury 112, it can be treated with suitable stem cells or a de-cellularization and re-cellularization regimen, or mixtures thereof, according to methods known to those with skill in the art. If injured organ 108 falls under category pneumonia 114, it can be treated with antibiotics, steroids, alveolar lavage, or mixtures thereof, according to methods known to those with skill in the art. If injured organ 108 falls under category edema 116, it can be treated with antibiotics, hyperperfusion techniques, hyper-osmotic agents, beta-agonists, or flow techniques, where, for example, optimal perfusion flow is about 40% of estimated cardiac output of the donor, or mixtures thereof, according to methods known to those with skill in the art. If injured organ 108 falls under category inflammation 118, it can be treated with anti-inflammatory agent, gene therapy, stem cell therapy, anti-coagulation therapy, or mixtures thereof, according to methods known to those with skill in the art. If injured organ 108 falls under category non-specific injury 120, it can be evaluated by techniques known to the skilled person to determine the best treatment options.

Transplantable organs 106 can also benefit from being subjected to an EVOP system (described below). Such a system can preserve and maintain transplantable organs 106 in order to ensure that they are in optimum condition for transplantation into a recipient. The EVOP system can also improve transplantable organs 106 to make them even better candidates for transplantation.

An ex vivo organ perfusion system of the present invention subjects a donor organ to a blood-less acellular normothermic perfusate. With this system, donor organ 102 can be perfused in an ex vivo circuit, providing an opportunity to assess and re-assess the function of donor organ 102 before transplantation. The EVOP can be used at all stages of process 100 to assist in the preservation, maintenance, repair, improvement, and/or assessment of an organ. For example, EVOP can be used soon after donor organ 102 has been excised from the donor, and can replace or supplement standard evaluation 104 of process 100. EVOP can also be used after standard evaluation 104 on both transplantable organ 106 and injured organ 108 in order to preserve, maintain, improve, assess and, in the case of injured organ 108, repair donor organs 102. With ex vivo organ perfused organs, organs are perfused, and in the case of lungs, are additionally ventilated, at body temperature to mimic physiologic conditions, which can preserve and maintain the organ, as well as allow the organ to be treated or to repair itself. Successful EVOP can restore the cell structure integrity and allow, for example, ZO-1 tight junction repair of donor organ 102. Organs subjected to EVOP can be preserved and maintained for 12, 24, 72 hours, or longer.

With reference to FIG. 2, an embodiment of an ex vivo organ perfusion system 200 is shown, where the organs in question are lungs. However, skilled persons will appreciate that other organs can be perfused using the ex vivo organ perfusion system 200, such as those mentioned above. In the embodiment shown, the ex vivo organ perfusion system 200 is a closed loop system. Also in the embodiment shown, donor organ 102 is represented by donor lungs 202. EVOP system 200 requires perfusate 218, which may comprise or consist of a commercially available solution, such as Steen Solution™, Perfadex™ solution or other solution suitable for perfusion according to the present invention. Steen Solution™ comprises calcium chloride, Dextran 40, Glucose, Human serum albumin, magnesium chloride, potassium chloride, sodium bicarbonate, sodium chloride, sodium dihydrogen phosphate, and water. It is preferable that the solution has a pH of about 7.4 (±0.3) and an osmolality of around 295±20 mOsm/kg. It will be recognized by the skilled person that solutions that do not comprise all of these ingredients, substitute ingredients, or have additional ingredients, may be suitable to use as perfusate 218. Other components can be used in perfusate 218 to either assist in the preservation, maintenance, improvement, or repair of donor organ 102. For example, heparin or the like can be used, such as, for example, sodium heparin, in an amount of, for example, 3,000 to 10,000 international units. Antibiotics can be added, such as, for example, cefazolin or Primaxin™, in an amount of, for example, 500 mg. Another example of a component that can be added to perfusate 218 are steroids, such as methylprednisolone (also known as Solumedrol™), in an amount of, for example, and 500 mg. It is preferred that perfusate 218 is acellular; that is, it does not contain or contains a minimal amount of red blood cells, particularly when donor organ 102 is one or two lungs.

The ex vivo organ perfusion system 200 of the current embodiment is designed to provide perfusate 218 to donor organ 102 in a beneficial and temperature-controlled manner. Referring now to FIG. 2, perfusate 218 is collected and/or stored in reservoir 216, which may have a soft or hard shell and can made of any suitable material, such as a laboratory or medical grade plastic. Reservoir 216 is connected to outlet hose 220, which in turn is connected to pump 214. Pump 214 can be a centrifugal pump, or any other pump suitable for facilitating the circulation of perfusate 218 through system 200. Pump 214 is connected to membrane gas exchanger 212 by hose 222. Membrane gas exchanger 212 can be, as in the embodiment shown, a hollow-fibre oxygenator and heat exchanger. Membrane gas exchanger 212 is also connected to deoxygenator gas tank 226 via gas line 224. Tank 226 houses gas that is suitable to substantially deoxygenate perfusate 218 while it passes through membrane gas exchanger 212 to decrease the pO2 to a range of about 30 mm Hg to about 80 mm Hg. The gas supplied by tank 226 is typically a gas mixture comprising about 6% oxygen (O2), about 8% carbon dioxide (CO2), and about 86% nitrogen (N2). The skilled person would understand that other gases or gas mixtures may achieve the result of substantial deoxygenation of perfusate 218 according to the present invention. Membrane gas exchanger 212 is also connected to heat exchanger 228, which maintains perfusate 218 at a desired temperature, such as at a temperature between about 20 degree Celsius and 38 degree Celsius. Most preferably, the temperature is about 37 degree Celsius.

Membrane gas exchanger 212 is also connected to leukocyte filter 210 by hose 230. During operation of system 200, perfusate 218 passes from membrane gas exchanger 212 to leukocyte filter 210 through hose 230. Leukocyte filter 210 reduces the amount of leukocytes located in perfusate 218 as it passes through leukocyte filter 210 by an amount in the range of 70% to about 100%. Leukocyte filter 210 is connected to cannula 208 in a manner that allows perfusate 218 to enter donor lungs 202 as described herein. Donor lungs 202 comprise pulmonary artery 204 and left atrium 206. Donor lungs 202 are transported from the donor (not shown) in a suitable manner and would typically be available for perfusion anywhere between immediately and to about 24 hours after being removed from the donor, more preferably within 12 hours. In the embodiment shown, pulmonary artery 204 is attached to pulmonary artery cannula 208 in a manner that allows perfusate 218 to flow through cannula 208 and into pulmonary artery 204 without unacceptable leakage. An exemplified manner of attachment is described further below.

Pulmonary artery flow of perfusate 218 is controlled by centrifugal pump 208 and measured using a flow meter (not shown), which in some embodiments can be an electromagnetic flow meter. The outflow of perfusate returns through left atrial cannula 232 to reservoir 216. Pulmonary artery and left atrial catheters 208 and 232 placed in situ continuously measure the pressures of the pulmonary artery and the left atrium of lungs 202. In the embodiment shown, lungs 202 are ventilated with ventilator 234, which, in the embodiment shown is an ICU-type ventilator.

In order to operate system 200, the steps taken generally include priming the close-looped system shown in FIG. 2, preparing the organs, initiating EVOP, maintaining a steady-state phase of EVOP, assessing the organs, and terminating EVOP.

To prime the circuit, system 200 is primed with a suitable amount of perfusate 218. The system can be primed with, for example, 1 to 2 liters of perfusate 218. The amount required can be determined by the skilled person. In some embodiments, ex vivo organ perfusion system 200 can be primed with about 1 or 2 liters of perfusate.

Generally, prior to perfusion of donor organ 102, donor organ 102 is prepared for ex vivo organ perfusion system 200. By way of example, the preparation of donor lung 202 is described for use with system 200; however, skilled persons will understand that other organs can be prepared and perfused with ex vivo organ perfusion system 200.

After donor lung 202 is retrieved from the donor, the heart is excised from the heart-lung block. The left atrial appendage is trimmed off and left atrial cannula 232 is sewn to the left atrial cuff of left atrium 206. In some embodiments, left atrial cannula 232 can be funnel-shaped with a built-in pressure monitor. By inserting and sewing left atrial cannula 232 to left atrium 206, a consistent outflow drainage of perfusate 218 can be provided during perfusion using system 200. This can create a positive left atrial pressure within a range of about 3 mmHg to about 5 mmHg. Pulmonary artery cannula 208 is substantially similar to left atrial cannula 232 and is inserted into and sewn to the pulmonary artery 204. In some embodiments, left atrial and pulmonary artery cannulas 232 and 208 can be trimmed to fit left atrium 206 and pulmonary artery 204.

After cannulas 208 and 232 have been inserted into and sewn to the pulmonary artery 204 and left atrium 206, a back-table retrograde flush is performed, in some embodiments using about 500 ml of Perfadex™ under gravity drainage at 30 cm. During this procedure, any potential perfusate leaks from the pulmonary artery or left atrial cannulas 208 and 232 can be checked and secured if required.

During operation of system 200, donor organ 102 can be housed in ex vivo chamber 236, such as a commercially available brand, (e.g., XVIVO), which has suitable openings for necessary equipment, such as pulmonary artery cannula 208, left atrial cannula 232, and ventilator hose 238. Chamber 236 can assist in maintaining donor organ 102 contaminant-free and temperature regulated. Before transferring lungs 202 to chamber 236 of system 200, the trachea (not shown) of lungs 202 is opened and bronchial cleaning of secretions is performed. Further, an endotracheal tube, in some embodiments having an inner diameter of about 9 mm is inserted in the trachea and secured circumferentially, in some embodiments using umbilical tape.

In some embodiments, during operation of system 200, a slow retrograde flow is optionally initiated to de-air pulmonary artery cannula 208. Once de-airing is complete, pulmonary artery cannula 208 can be connected to ex vivo organ perfusion system 200 and anterograde flow is initiated, in some embodiments at a flow rate of about 150 mL/min. During this time, perfusate 218 can be at room temperature.

In order to initiate system 200, the temperature of perfusate 218 can be incrementally increased to body temperature, for example 37 degrees Celsius, in some embodiments over a time period of about 30 minutes. The flow rate of perfusate 218 can then be incrementally increased, for example up to 1,500 mL/min over the next 30 minutes. However, prior to increasing the flow rate, the pressure readings of pulmonary artery 204 and left atrium 206 should be checked in order to prevent hydrostatic damage of lungs 202. For example, it is desirable that the atrial pressure of left atrium 206 is in the range of about 3 mm Hg to about 5 mm Hg and the arterial pressure of pulmonary artery 208 is in the range of about 10 mm Hg to about 15 mm Hg.

Once a temperature of about 32 degrees Celsius is reached, in some embodiments 20 minutes after the initialization of perfusion, ventilator 234 can be started and flow rate of perfusate 218 can be gradually increased. When ventilator 234 is started, the flow rate should be at least 20% of the target flow rate. The flow rate can continue to be increased to about 1,500 mL/min over a period of about 40 minutes. Once the desired flow rate of perfusate 218 has been reached, the flow of deoxygenation gas from tank 226 can be started. In some embodiments, the flow of the\'deoxygenation gas can be at a rate of between about 0.5 and about 1 liters per minute, more preferably about 1 liter per minute, and can be titrated to maintain the inflow of perfusate 218, in some embodiments between about 35 and about 45 mm Hg.

Once the temperature of perfusate 218 reaches body temperature (for example, about 37 degrees Celsius), the flow can continue to be increased stepwise over a period of time, such as about 30 minutes, to a desired flow rate. In some embodiments, the desired flow rate will be a predetermined percentage of predicted cardiac output, in some embodiments 40%; however, skilled persons will appreciate that the target can be calculated from the size of the lung capacity of donor lungs 202. Recruitment maneuvers can be used to recruit regions of lung atelectasis, in some embodiments to a maximum of 25 cm H2O of peak airway pressure.

An exemplary schedule for initialization of ex vivo organ perfusion system 200, during the first hour of perfusion, is shown in Table 1 (below) shows one suggested perfusion initialization schedule.

TABLE 1 Strategy for Initiation of Ex Vivo Lung Perfusion Perfusion time (min) 0 10 20 30 40 50 60 Perfusion temp. (° C.) 20 30 32-35 37 37 37  37 Flow (% calculated flow) 10 10  20 30 50 80 100 i.e.: 1,500 ml/min (ml) 150  150  300 450  750  1,200   1,500   Ventilation None None Start Recruitment Gas exchanger None None Start Left atrial pressure (mmHg) 3-5 3-5 3-5 3-5 3-5 3-5 3-5

Once initialization is completed, ex vivo organ perfusion system 200 is operated in a steady-state or maintenance period for a maintenance period of time. The maintenance period can also be considered the preservation and/or assessment period. In this phase, a lung-protective strategy of mechanical ventilation is used, in some embodiments using a tidal volume of between about 6 to about 8 mL/kg, a positive end-expiratory pressure (peep) of about 5 cm H2O, a respiratory rate of 7 breaths per minute, and a fraction of inspired oxygen of about 21%. During steady-state, recruitment maneuvers can be performed every hour, in some embodiments to a peak airway pressure of about 25 cm H2O. Imaging of the lung may occur during this period. For example, x-rays may be taken periodically, such as at about 1 hour and at about 4 hours.

During initialization and the steady-state operation of ex vivo organ perfusion system 200, the positive left atrial pressure can be maintained between about 3 mm Hg and about 5 mm Hg by adjusting the height of reservoir 216. In some embodiments, during initialization the revolutions per minute of pump 214 can be set to about 550 revolutions per minute and a clamp on left atrial cannula 232 is opened. In such embodiments, a slow trickle of perfusate 218 can begin to flow out of the left atrial cannula 232 and the revolutions per minute of pump 214 can be increased or decreased from this starting point in order to optimize flow. Skilled persons will appreciate that different tube lengths of left atrial cannula 232 can change the starting set point for the revolutions per minute of pump 214.

The flow rate of perfusate 218 is maintained at a calculated flow rate, which can be determined based on a predefined percentage of an estimated cardiac output, in some embodiments being about 40%. Skilled persons will appreciate that most lungs can be perfused at a non-pulsatile flow rate while generally maintaining acceptable low pulmonary artery pressures, in some embodiments in the range of about 10 mm Hg to about 15 mm Hg. In some embodiments, the cardiac output can be estimated at 100 mL/kg, and in other embodiments, for example in human lungs, the cardiac output can be estimated as 3 times the body surface area (assuming the target cardiac index is three).

Exemplary conditions for the operation of the steady-state phase of ex vivo organ perfusion system 200 are show in Table 2 (below). In some embodiments, the amount of perfusate 218 passing through deoxygenater 212 is in the range of about 50 mL to about 500 mL per hour. In a preferred embodiment, about 250 mL of perfusate 218 is circulated through system 200 every hour. At this rate, perfusate 218 can be exchanged and replaced by fresh perfusate components which have been metabolized, and which can maintain glucose and other nutrient levels. In other embodiments, every hour during the steady-state phase of ex vivo organ perfusion system 200, 500 mL of the circulated perfusate 218 can be removed and replenished with 500 mL of fresh perfusate 218.

Donor organs can be preserved, assessed, and/or maintained in this steady state for a maintenance period of up to 24 hours, more preferably up to 8 hours, and even more preferably, up to 3 hours.

TABLE 2 EVLP Maintenance Strategy-Settings Measure Setting Tidal volume 6-8 ml/kg

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