The current techniques of preservation of organs to be transplanted are based on the cooling (hypothermia), and they present problems of difficult or impossible solution: little time of preservation; waste of available organs; damages taken place by the ischemia; death of patient in waiting lists for lack of organs; infections; immunological rejections; lingering periods of hospitalization; very high costs.
Applying to the study of each one of the involved stages the method of suitable reasoning suggested by the Postulate of the Maximum Limit of Optimization (MLO) (1), it is demonstrated that in spite of the improvements that will be incorporate to the hypothermic techniques they won't be been able to reach the wanted good results.
According to the postulate, to have better results Conceptual and Transcendent Changes (CTC) they should be carried out: for this reason, in opposition to the preservation techniques in cold and annulment of the circulation, it is intends to maintain the organs to preserve functioning in normothermia (to the normal temperature of the body).
Applying this new technique the organs will have a smooth transition from the donor to the receptor, without interrupting the circulation and maintaining the conditions of temperature and functioning, characteristic of the organ. The ischemia will be eliminated and inside the Normothermic Preservation Device the organs will have a period of preservation remarkably prolonged. Before attempting the transplant the organ will be adapted within the PRESERVATION DEVICE, so that the problems of rejection suffer them the implant instead of suffering them the patient-receptor.
It will be possible to have banks with an immediate availability of organs, new industries would be created for the production of the Preservation Devices and a new medical discipline would be “Specialist in Organs Preservation”.
Although some comments and examples are referred to the heart, the described concepts are applicable to all the organs that can be transplanted.
The global analysis of a complex project can be very difficult and conflicting. Considering that trying to arrive to the desired result of a project usually requires a logical sequence of stages (2), the problem of the preservation by means of hypothermia was studied trying to each one of its stages for separate.
It is generally guided to terminal patients with a social structure of support that assures the execution of the medical orders in the postoperative (4). The selected receptors are included into a waiting list, but a high percentage of them die for not being on time donors or for failures in the transplants (4,5,6,7,8). The necessary histocompatibility tests are difficult to carry out and perhaps for the on urgencies some studies are not completed (4). When not being able to be preserved the organs during more time they diminish the probabilities of the terminal patients, while the rigid selection approaches prevent patients serious not terminals to improve their quality of life (4). The MLO depends here on the impossibility of being able to satisfy all the patients.
One of the main problems to make transplants is the lack of appropriate organs (5,7,9,10). The factors that limit the selection of the donors are the general condition of the donors and their age (4). In general, donors are accepted that they don't exceed certain age limit, although donors of more age exist potentially capable. Donors deceased are looked for in accidents and it is not to use donors' organs that died for illness, maybe for the impossibility of determining the conditions of the usable organs (4,5,6,11). For the short periods of preservation, it is possible that available organs are discarded. In this stage, the MLO strongly depends on the short period of preservation of the organs.
In order to minimize the time of ischemia (12) they should be planned and to synchronize the stages to transport the organ from the donor's place until the place of the receptor: to inform to different Police Departments to obtain their help whit the traffic, available vehicles and drivers, to contact with airlines and to have availability of transportations, documentation for international trips, etc. (4). There exists a MLO for each one of the planning that they are carried out, those that depend of incontrollable aleatory factors. In the case of some transplants the receptor should be anesthetized when extracting the organ; starting from that moment the surgery will be timed to carry out on the receptor while they awaiting the donated organ arrives, avoiding irrevocable surgical maneuvers (4). Brief periods of ischemia (e.g.: lung transplant or cardiopulmonary transplant) they cause dysfunctions after the transplant; for that reason the ideal would be to carry out the preparations of the receptor and of the donor in the same moment and in the same place (4). As the Current Performing Conditions (CPC) in this stage are very unfavorable, the MLO (total of the stage) it becomes critical.
In order to proceed to the ablation of the organ different veins and arteries are ligate and sectioned, being annulled the possibilities of circulation of blood (ischemia) (4). As soon as ischemia appears, damages taken place by chemical reactions whose speed depends on the temperature arise, for what the current techniques of preservation of organs are based on the cooling (4,13). When the temperature is lowered the damages would be decrease, and there are a bigger quantity of time before serious damages take place. However, they may exist irreversible damages, which have not been observed, whose effects will be evidenced later on (4,13). During years the donated organs functioned to oneself temperature and they were fed and circulated by a continuous flow of blood. For example, to the effects of the transplant, the heart it is stops it abruptly in diastole, the circulation is interrupted and it replaces it for a perfusion of cold liquids of different composition: the temperature is lowered in very little time from + 37°C to + 4°C (4,5,12,13,14). Different elements are applied to the organ to try to maintain it under control (potassium, procaine, substrate, phosphates, blockers of the calcium way, osmolarity conservatives, et cetera). These maneuvers are contrary to the nature of any organ and they reduce at very low levels the values of the associate MLO.
It is takes place from the extirpation of the heart until the immersion of the implant in a means of storage for cold. The warm ischemia is the most harmful: the loss of vitality of the cells prevents to the organs to recover the sanguine flow when the circulation is restored (4,15). As it is indispensable to reduce the duration of this stage but in turn certain time is needed for the preparation of the organ to transplant, the best results that they can be obtained under the Current Performing Conditions (CPC) they will depend on not controllable aleatory factors (surgeons' ability or fatigue, et cetera).
It is appears when the organ remains in cold deposit, during the transportation (4). This time should be short, for what the distances are limited to transfer the organ and the histocompatibility tests (13). A simple method of preservation in hypothermia, but with limitations, it consists on introducing to the heart inside an appropriate solution (e.g.: Solution of Collins, Solution of the University of Wisconsin). Another method, the continuous perfusion with cold solutions, improves the survival of the implant during longer periods but it requires of special medical gears (4,13,15). As the preservation method it could depend on the duration of the warm ischemia, the MLO corresponding to the cold ischemia would be subordinate to facts taken place in another stage and outside of its control. They also have influence on this MLO the additional lesions taken place by the cold: turgescence of cells, lesions in the cellular membrane, inhibition of the carrier enzymes, losses of potassium, (4,12,15). Improvements in the hypothermic technical and the sterile solutions allowed increasing the times of preservation but without reaching to satisfy the existent necessities. According to the current concepts of preservation for cold, a more longer period of storage would only be obtained with temperatures under 0°C: but in carried out experiences maintaining these conditions, it was almost impossible to get an appropriate preservation of the organs (4). Everything indicates that it is been very near the MLO referred to preservation of organs by hypothermia, and that this MLO is very far from the required solution.
It lapses since the organ of the cold deposit is extracted until its functioning is renewed (4). This is a vulnerable period because when warming the organ, quickly their energy reserve they are drained: the form of trying to compensate this situation is by means of the application of several medications (4). The MLO will also be conditioned by the gradient of temperature and the answer to the used medication.
The organism considers harmful to all that comes out and to defend it produces an immunological answer: so that the transplant is accepted it should be disable the immunological system of the receptor temporarily. In most of the cases immunossuppresive drugs should be taken of for life. If the organs are seemed genetically (a brother's organ) (4, 9) the probabilities of success are bigger, but this situation it is presented only few times. The application of immunosuppressive drugs can produce effects nephrotoxic and/or hepatotoxic while the medication changes usually increase the percentages of rejection (4,5,12). The transfusion of blood coming from the donor could attenuate the immune reaction to the implant, but other illnesses can be presented (hepatitis, AIDS, et cetera). The MLO associated to the treatment of the rejection depends from the answer to the medication and of the little available time.
In immunosuppressed individuals the infections are habitual and they can end up being serious, being one of the causes more common of death in having transplanted of the heart. It requires the application of antibiotics of broad-spectrum and constant surveillance (4).
Donated Organ Infections.
Under certain conditions, infections inherent of the donated organ can be presented, those that are treated administering medications to the receptor (4).
The patient's cares and controls.
The transplants require of much personal specialized to give a continuous attention to the patient: surgeons, cardiologists, anatomopathologists, infectiologists, specialized infirmary (4). During all the stages the patient receives great quantities of medications and must be permanently controlled so as to detect infections and rejections (4,6,11,16). The application of many drugs during all the stages, including antagonistic drugs, may produce non-desirable secondary effects. The hospitals should have the necessary control materials, with the intensive care units and the transplantation units, with possibility of maintaining the sterile isolation. The surgical tasks and those of medical aid, the intensive surveillance and the long periods of hospitalization and recuperation make that the costs are high (4). Due to the complexity of the required stages it is difficult to believe that partial improvements may significantly reduce costs. The MLO associated to the expenses, limits each aspect referred to the transplants.
The total MLO depends on the MLO related to each stage of the transplants. It is proven that the techniques for cooling preservation has reached their own MLO, the one that is far from the desired result: then, it is doesn't make sense continue developing new improvements on the cooling techniques and it is emphasized about the necessity of incorporating Conceptual and Transcendent Changes (CTC).
During the studies indeterminations were detected among the specialists, what confirms the convenience once again of incorporating CTC: (i) for some the current storage is correct, but others claim for more times of preservation (17); (ii) it is justified the use of the techniques based on the cold, but it was demonstrated that the organs recovered better at higher temperatures (18); (iii) they are related the changes with enormous impossible machines, without considering the advances in miniaturization, microelectronics and computation.
Well-known the necessity to carry out CTC it is thinking about different solutions and it is analyzed them to applying the concepts of the postulate repeatedly. The author proposes as hypothesis that the organs to be preserved stay functioning in normothermia: verifying this solution could be proven that in theory the problems disappear and additional benefits are obtained.
THEORETICAL CHARACTERISTICS OF THE NORMOTHERMIC PRESERVATION DEVICE
The application of the normothermic techniques is based on the development of the Normothermic Preservation Device. The purpose of the Device is to simulate the natural environment of the organ and to facilitate the flow of the blood and of other liquids (5). The final objective is to achieve that the organ doesn't detect differences among the donor's body (in normal operation) and the Device. Although each organ type will need a different Device, they will exist common characteristics.
In schematic form, the Device would have the following elements and characteristics: space for the organ; maintenance of the organ in the darkness to avoid undesirable effects of the light upon the organ (photolysis, photomagnetism, photochromogenicity) (12); temperature conditioner with sensors, to maintain the group temperature similar to the normal temperature of the body; bombs that maintain the appropriate pressure of the fluids and of the organ (maybe an extra-pressure on the organ could help to its preservation); oxygenator (14); maintenance area to inspect the organ, to add the necessary medicines and the nutriments to the blood (anticoagulants, hormones), extraction of samples for analysis and reinstatement or substitution of the sanguine volume; pacemakers to maintain the heart rhythm and, in other organs, to reinforce the circulation beating rhythms (4); detectors for monitoring; connection elements, to be connected first to the donating one and then to the receptor; electrical supply from the network and from battery or generator designed for this purpose.
Most of the above elements already exist at the moment (left ventricular assist device, rotating disk, blood pump, oxygenator, et cetera) and their size and weight can be modified to adapt them to this new application (12,15).
PROPOSED NORMOTHERMIC TECHNIQUES
The main aim is to achieve that the organ to transplant makes a smooth transition from its ablation (in the donor) until its reimplantation (in the receptor). If during this transition the organ could continue functioning its lesions they would usually decrease and it would maintain its energy reserves within reasonable limits, without necessity of external contributions or with minimum necessities (4,13). The traumatisms should also be eliminated that could damage the structure of the organ or decompensate its functioning. The circulation should not be interrupted and they should be maintained approximately constant the temperature and the operation parameters characteristic of each organ (e.g.: to regulate the heart rhythm by means of pacemakers and to maintain the gradients of pressure between the auricles and the ventricles) (14).
The normothermic techniques will make possible the existence of “organs banks” with immediate availability of organs (10), and perhaps they would not be used more the hopelessly waiting lists. The illicit obtaining of organs and their traffic would not be a lucrative business, for what this topic would no longer worry.
With the organ normally functioning within an environment that it is simulates their habitat, the period of preservation will reach unsuspected levels. The total suppression of the ischemia will eliminate the related damages and it will limit the application of compensating drugs. When having more available time, the legal proceedings will be facilitated.
The adaptation of the patient to the new organ will have unprecedented aspects because it is will be carried out, before attempting the transplant, within the Preservation Device: the problems of rejection will suffer them the organ instead of suffering them the patient-receptor. The infections of the implant (4) they will be treated locally within the Device, without affecting to the future receptor.
The advantages and the future possibilities opened up by this new concept are enormous: it could decrease significantly the deactivation time of the receptor’s immunological system, and perhaps the studies and experiences could make unnecessary such deactivation. Having the organ within a controllable enclosure, experiences they could be made trying to find the limits of their immunological barrier: maybe perturbing their molecular balance with pressures and/or temperatures and/or drugs and at the same time making that the blood of the receptor circulates through the organ, could they resemble each other (¿re-programing?) the parameters of the organ to those of the patient-receptor... then, for the immunological system of the receptor, the implant would not be a strange... They would also be applied to the organ the necessary genetic therapies to avoid the rejection, without risks for the patient-receptor (although organs of animals are used).
They would diminish the graveness of the infections and their quantity, the secondary effects for application of drugs and the periods of hospitalization and recovery. When increasing the quantity of receptors (terminals or not) that would have access to the organs transplant to survive or to improve their quality of life (19,20), a gradual decrease of the costs would take place.
The concept of the Normothermic Preservation Device is applicable to all organs that can be transplanted. For example, the biliary atresia in the children is treated with liver transplant, but there are not donors with the appropriate age. The solution is the hepatic reduction, separating adult's compatible liver in 2 or more fractions and using it in more than a transplant (4,12) (the Device would allow its preservation).
For years they are carried out experiences with xenografts (4,5,9,12). The use of the Preservation Device would facilitate the controls and the studies to perfect this technique. In the future, the artificial organs (5) that are in developing they could be adapted to each user within the Device of Preservation.
It will be less demanding since when increasing the periods of preservation there will be time to cure dysfunctions of the organ, to carry out studies of crossed histocompatibility, et cetera. Less limitative approaches will be used that the current ones, including donors of more age and still those that die for some illness that doesn't affect direct and definitively to the organ. After the declaration of death (4) and when it is possible, they will be continued using the support systems to the life to maintain the functioning of the organs to transplant. It will be to incorporate each organ to transplant quickly within their corresponding Device of Preservation. The possibility to keep the organs for long periods will promote the promulgation of laws regulating its obtainment. In this way, the organs in stock will be able to satisfy the demand.
Before proceeding to the ablation of the organ, it will be connected to the Device of Preservation (4) forcing their operation to normal manner. They will become to circulate the fluids within the Device and depending on the state of the organ anticoagulants, medications and all elements will be added that can improve the donor's blood. When the organ reaches its normal functioning due to the contribution of the Normothermic Device of Preservation, the ablation of the organ will be performed and it is will make comfortable it in convenient form within the Device.
Organ Preservation within the Normothermic Preservation Device.
With the organ within the Device the controls and the corresponding studies will be made and the medications that the organ needs will be applied. The donor's blood could be conserved, although the use of substitutes would have some advantages: not toxic, with good tolerance, easy to conserve and they don't transmit illnesses (easy to sterilize). The organ will be preserved in normal functioning within the Device until the moment to adapt it to a patient-receptor.
Adaptation of the Organ to the Patient-Receptor.
It will be partially replaced the donor's blood or their substitutes with the blood of the patient-receptor (exsanguinotransfusion) (12,21). It is let him to circulate the necessary time to allow the adaptation of the organ and more blood of the receptor will be added until replacing totally to the original liquids. The state of the organ will be controlled to detect symptoms of rejection. For brief periods the immunological system of the organ could be disabled and it is in this stage where would be made the maneuvers tending to equal the immunological parameters from the organ to those of the patient-receptor. The functioning of the organ with the receptor’s blood should stay until it becomes stable, moment starting from which the transplant will be attempted.
It is connected in parallel (4) the organ donated with the organ to replace, without disconnecting it of the Device of Preservation. The connection should be maintained until verifying that irreversible acute rejection doesn't exist.
- Postulate of the Maximum Limit of Optimization (MLO): logical-mathematical procedure.
- Crick F: What Mad Pursuit. Tusquets Editores, Barcelona, 1989, p. 85.
- Ibid 2., p. 81.
- Barber R, Cabrol C, Cohen Z et al: The Surgical Clinics of North America, Organ Transplant. WB Saunders Co/EMALSA SA, Madrid, Volume 3,1986.
- Perrone SV: Heart Transplants in Argentina and in the World. Federación Argentina de Cardiología 4:281-285, 1991.
- Favaloro RR, Perrone SV, Gómez CV et al: Cardiopulmonary Transplant. Federación Argentina de Cardiología 4:479, 1993.
- Vargas FJ, López R, Díaz S et al: Pediatric Heart Transplants in Argentina. Federación Argentina de Cardiología 4:492, 1993.
- Ibid 7: First Pediatric Cardiopulmonary Transplant in the Argentina. Federación Argentina de Cardiología 4:492, 1993.
- Wayne Flye M: Principles of Organ Transplantation, Transplantation History, Chapter 1°. Philadelphia Saunders, 1989.
- Cohen LR: A market proposal for increasing the supply of cadaveric organs. Clinical Transplantation, 5°: 467-474, 1991.
- Favaloro RR, Perrone SV, Comignani P et al: Heart Transplants. Federación Argentina de Cardiología 4:479, 1993.
- Dorland's Illustrated Medical Dictionary. EMALSA / Mc GRAW–HILL, Madrid, 1988, 9° edition.
- Minten J, Flameng W, Dyszkiewics W: Optimal storage temperature and benefit of hypothermic cardioplegic arrest for long-term preservation of donor hearts. Transplant Int 1: 19-25, 1988.
- Yacone LA: Cardiovascular Problems. Medical Econ Co, NJ, 1983.
- Southard JH, Belzer FO: Principles of Organ Transplantation, Chapter 10, Organ’ Conservation. Philadelphia, Saunders, 1989.
- Scientific Tables, CIBA-GEIGY S.A., Basle, Switzerland, 1973; pág.645.
- Southard JH and Belzer FO: Principles of Organ Transplantation, Cap.10, Organ’ Conservation. Philadelphia Saunders, 1989, pág. 200.
- Minters J, Flameng W & Dyszkiewics: Transplant Int 1:19-25, 1988.
- Dantur J, Barico L, Marañón R et al: Heart Surgery in the 8° and 9° Decade of the Life, XIV National Congress of Cardiology. Federación Argentina de Cardiología TL-21, P-21, 1994.
- Ficarra A, Caramutti E, Tomasini M, Leone L: Heart Surgery in Patient bigger than 75 Years, XIV National Congress of Cardiology. Federación Argentina de Cardiología TL-22, P - 22, 1994. 21. Moullec J: Les Groupes Sanguins. Presses Universitaires, Paris, 1964.
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