Language: Inglés
Current techniques for the conservation of organs to be transplanted based on cooling (hypothermia), present difficult problems or impossible to solve: low shelf, waste of available organs, damage caused by ischemia, death of patients on waiting lists for lack of organs, immune rejection, infections, periods of hospitalization, high costs.
Applying to study each of the stages involved the method of reasoning given by the postulate of Ceiling Optimization (LMO) (1), shows that despite the improvements that are incorporated to hypothermic techniques may not achieve the desired optimum results.
According to postulate, for best results should be made and Transcendent Conceptual Change (CST) : for this reason, as opposed to the techniques of cold storage and withdrawal from circulation, it is proposed to keep working bodies in normothermia (A normal body temperature).
Applying this new technique bodies have a smooth transition from the donor to the recipient without interrupting the flow and keeping the temperature and operating conditions typical of the organ. Ischemia will be removed and within Normothermic Conservation Device bodies have a significantly higher shelf. Before attempting the transplant is performed adapting the body within the Conservation device so that the problems of graft rejection is sustained instead of suffering the patient-receptor .
banks will be possible to have immediate availability of organs would create new industries for the manufacture of conservation devices and a new medical discipline would be "organ preservation specialist."
CURRENT TECHNIQUES
Although some comments and examples are referred to the heart, the concepts described are applicable to all organs can be transplanted.
global analysis of a complex project can be very difficult and contentious. Whereas trying to reach the desired outcome of a project usually requires a logical sequence of steps (2), the issue of conservation by hypothermia was studied by treating each of its separate stages.
Selection of patients-recipients.
is generally aimed at terminally ill patients with a social structure of support to ensure compliance with medical orders in the postoperative period (4). The selected recipients are added to waiting lists but a high percentage die from donors found no time or failure in transplantation (4,5,6,7,8). The necessary tests are difficult to perform histocompatibility and perhaps for emergencies at play are not completed studies (4). Unable to preserve organs longer reduce the chance of dying patients while the rigid selection criteria prevent serious non-terminal patients can improve their quality of life (4). The LMO depends here of the impossibility of satisfy all patients.
donor selection.
One of the main problems for transplants is the lack of appropriate bodies (5,7,9,10). The factors that limit the selection of donors are donors overall and age (4). In general, donors are accepted not to exceed a certain age limit, although there are older donors potentially suitable. Deceased donors are sought in accidents and try not to use organs from donors who died of disease, perhaps by the inability to determine the status of usable organs (4,5,6,11). For the short retention periods, may be disposed available organs. At this stage, the LMO short depends on the preservation of organs. Process
preoperatively.
To minimize ischemic time (12) should plan and synchronize the stages for carrying the body from the place of the donor to the receptor site: notify various police to enlist their help in traffic, vehicles and drivers available contacts with airlines and availability of media, international travel documentation, etc. (4). There is a LMO for each of the schedules are made, which depend on random factors not controllable. For some transplant recipient must be anesthetized to remove the organ, from that moment be timed surgery to be performed on the receiver while awaiting the arrival of the donated organ, thus avoiding irreversible surgical procedures (4). Brief periods of ischemia (eg lung or heart-lung transplantation) cause dysfunction after transplantation, so that the preparations of the recipient and the donor should be performed at the same time and same place (4). As Existing Conditions of Production (CRE ) at this stage are very unfavorable, the LMO (total phase) is critical.
ablation of the organ.
As a prelude to the ablation are linked and divided various veins and arteries, canceling the possibility of blood flow (ischemia) (4). There is hardly arise ischemic damage by chemical reactions whose speed depends on temperature, so the current conservation techniques are based on organ cooling (4.13). Lowering the temperature reduces damage and have more time before serious injury, irreversible damage can be observed, the effects will be noted below (4.13). For years they worked donated organs to the same temperature and were fed and circulated by a continuous flow of blood. For example, for the purposes of transplantation, the heart will suddenly stop in diastole, the flow is interrupted and replaced by an infusion of cold fluids of different composition: the temperature drops very quickly from + 37 ° C to + 4 ° C (4,5,12,13,14). Apply different elements to try to keep the body under control (potassium, procaine, phosphates, substrates, blockers of calcium channels, conservatives in osmolarity, etc.).. These maneuvers are contrary to the nature of any organ and reduced to very low values \u200b\u200bassociated LMO.
Warm Ischemia.
removal occurs from the heart to the immersion of the graft in a cold storage medium. Warm ischemia is the most damaging: the loss of vitality of the cells prevents blood flow to recover organs when circulation is restored (4.15). As it is essential to reduce the duration of this stage, but in turn needs some time to prepare the organ to transplant, the best results to be obtained under Making Existing Conditions ( CRE) will depend on uncontrollable random factors ( skill or fatigue surgeons, etc.)..
Cold Ischemia.
appears when the body remains in cold storage during transport (4). This time should be short, so the distances are limited to transport the organ and histocompatibility testing (13). A simple method of preservation in hypothermia, but with limitations, is the introduction of the heart within a suitable solution (eg Collins Solution, Solution of the University of Wisconsin). Another method, continuous perfusion with cold solutions, improves graft survival for longer periods but it requires special equipment (4,13,15). As the method of preservation may depend on the duration of warm ischemia, the LMO for cold ischemia would be subordinate to events occurring in another stage and out of your control. Also influence the LMO additional injuries caused by the cold, cell turgor, lesions in the cell membrane, inhibition of transport enzymes, potassium loss (4,12,15). Improved techniques and sterile solutions hypothermic allowed to increase storage times without reaching to meet existing needs. According to current concepts of preservation by cold storage longer only be obtained with temperatures below 0 ° C, but on experiences under these conditions, it was almost impossible to get a proper conservation bodies (4). It appears that you are very near the LMO referred to organ preservation by hypothermia and that LMO is far from the required solution.
Surgical Ischemia.
It leads from the body is removed from cold storage until it resumes (4). This is a vulnerable period for heating the body quickly deplete its reserves Energy: how to try to offset this situation by implementing various drugs (4). The LMO will also be influenced by the temperature gradient and the response to the medication used.
Rejection therapy.
The agency considered detrimental to everything that comes from outside and to defend causes an immune response: for the transplant to be accepted must temporarily disable the recipient's immune system. In most cases it should take immunosuppressant drugs for life. If organs are genetically similar (body of a brother) (4.9) the odds of success are greater, but this seldom occurs. The application of immunosuppressive drugs can cause nephrotoxicity and / or hepatotoxic while medication changes tend to increase the percentage of rejection (4,5,12). Transfusion of blood from the donor could dampen the immune response to the graft, but there may be other diseases (hepatitis, AIDS, etc.).. The LMO associated with treatment of rejection depends on the response to medication and the time available.
Receiver Infections.
infections in immunocompromised individuals are common and can become severe being one of the most common causes of death in heart transplant recipients. This requires the application of broad spectrum antibiotics and continuous monitoring (4).
donor organ infections.
Under certain conditions, infections may own the donor organ, which is fighting administering medications to the receiver (4).
patient care and controls.
transplants require much expertise to give continuous attention to the patient, surgeons, cardiologists, pathologists, infectious disease, nursing (4). During all stages the patient receives large amounts of drugs and is permanently controlled for infection and rejection (4,6,11,16). The application of many drugs at all stages, including antagonistic drugs can produce unwanted side effects. Hospitals must have the necessary control equipment, intensive care units and transplant and ability to maintain the sterile barrier. The surgical work and health care, intensive surveillance and long periods of hospitalization and recovery make the costs are high (4). Because of the complexity of steps required is difficult to partial improvements of current techniques may lower costs. The LMO limited costs associated with every aspect referred to transplantation. LMO
The total depends on the LMO each intervening stage. It is found that cold preservation techniques have reached LMO, which is far from the desired result, then, does not make sense to keep developing new improvements on the cooling techniques and emphasizes the need to incorporate, Transcendent Conceptual Changes ( CST). In studies
uncertainties were detected among specialists, confirming once again the desirability of incorporating CCT : (i) for some current storage is correct, but others call for greater storage times (17), (ii) justified the use of techniques based on the cold, but it was found that the bodies are recovered better at higher temperatures (18 ), (iii) are changes with huge machines unworkable, regardless of advances in miniaturization, microelectronics and computer . Known
the need arise CST different solutions and analyze repeatedly applying the concepts postulated. The author proposes the hypothesis that the bodies remain to be preserved operating in normothermia: verifying this solution theory was proved that the problems go away and additional benefits.
global analysis of a complex project can be very difficult and contentious. Whereas trying to reach the desired outcome of a project usually requires a logical sequence of steps (2), the issue of conservation by hypothermia was studied by treating each of its separate stages.
Selection of patients-recipients.
is generally aimed at terminally ill patients with a social structure of support to ensure compliance with medical orders in the postoperative period (4). The selected recipients are added to waiting lists but a high percentage die from donors found no time or failure in transplantation (4,5,6,7,8). The necessary tests are difficult to perform histocompatibility and perhaps for emergencies at play are not completed studies (4). Unable to preserve organs longer reduce the chance of dying patients while the rigid selection criteria prevent serious non-terminal patients can improve their quality of life (4). The LMO depends here of the impossibility of satisfy all patients.
donor selection.
One of the main problems for transplants is the lack of appropriate bodies (5,7,9,10). The factors that limit the selection of donors are donors overall and age (4). In general, donors are accepted not to exceed a certain age limit, although there are older donors potentially suitable. Deceased donors are sought in accidents and try not to use organs from donors who died of disease, perhaps by the inability to determine the status of usable organs (4,5,6,11). For the short retention periods, may be disposed available organs. At this stage, the LMO short depends on the preservation of organs. Process
preoperatively.
To minimize ischemic time (12) should plan and synchronize the stages for carrying the body from the place of the donor to the receptor site: notify various police to enlist their help in traffic, vehicles and drivers available contacts with airlines and availability of media, international travel documentation, etc. (4). There is a LMO for each of the schedules are made, which depend on random factors not controllable. For some transplant recipient must be anesthetized to remove the organ, from that moment be timed surgery to be performed on the receiver while awaiting the arrival of the donated organ, thus avoiding irreversible surgical procedures (4). Brief periods of ischemia (eg lung or heart-lung transplantation) cause dysfunction after transplantation, so that the preparations of the recipient and the donor should be performed at the same time and same place (4). As Existing Conditions of Production (CRE ) at this stage are very unfavorable, the LMO (total phase) is critical.
ablation of the organ.
As a prelude to the ablation are linked and divided various veins and arteries, canceling the possibility of blood flow (ischemia) (4). There is hardly arise ischemic damage by chemical reactions whose speed depends on temperature, so the current conservation techniques are based on organ cooling (4.13). Lowering the temperature reduces damage and have more time before serious injury, irreversible damage can be observed, the effects will be noted below (4.13). For years they worked donated organs to the same temperature and were fed and circulated by a continuous flow of blood. For example, for the purposes of transplantation, the heart will suddenly stop in diastole, the flow is interrupted and replaced by an infusion of cold fluids of different composition: the temperature drops very quickly from + 37 ° C to + 4 ° C (4,5,12,13,14). Apply different elements to try to keep the body under control (potassium, procaine, phosphates, substrates, blockers of calcium channels, conservatives in osmolarity, etc.).. These maneuvers are contrary to the nature of any organ and reduced to very low values \u200b\u200bassociated LMO.
Warm Ischemia.
removal occurs from the heart to the immersion of the graft in a cold storage medium. Warm ischemia is the most damaging: the loss of vitality of the cells prevents blood flow to recover organs when circulation is restored (4.15). As it is essential to reduce the duration of this stage, but in turn needs some time to prepare the organ to transplant, the best results to be obtained under Making Existing Conditions ( CRE) will depend on uncontrollable random factors ( skill or fatigue surgeons, etc.)..
Cold Ischemia.
appears when the body remains in cold storage during transport (4). This time should be short, so the distances are limited to transport the organ and histocompatibility testing (13). A simple method of preservation in hypothermia, but with limitations, is the introduction of the heart within a suitable solution (eg Collins Solution, Solution of the University of Wisconsin). Another method, continuous perfusion with cold solutions, improves graft survival for longer periods but it requires special equipment (4,13,15). As the method of preservation may depend on the duration of warm ischemia, the LMO for cold ischemia would be subordinate to events occurring in another stage and out of your control. Also influence the LMO additional injuries caused by the cold, cell turgor, lesions in the cell membrane, inhibition of transport enzymes, potassium loss (4,12,15). Improved techniques and sterile solutions hypothermic allowed to increase storage times without reaching to meet existing needs. According to current concepts of preservation by cold storage longer only be obtained with temperatures below 0 ° C, but on experiences under these conditions, it was almost impossible to get a proper conservation bodies (4). It appears that you are very near the LMO referred to organ preservation by hypothermia and that LMO is far from the required solution.
Surgical Ischemia.
It leads from the body is removed from cold storage until it resumes (4). This is a vulnerable period for heating the body quickly deplete its reserves Energy: how to try to offset this situation by implementing various drugs (4). The LMO will also be influenced by the temperature gradient and the response to the medication used.
Rejection therapy.
The agency considered detrimental to everything that comes from outside and to defend causes an immune response: for the transplant to be accepted must temporarily disable the recipient's immune system. In most cases it should take immunosuppressant drugs for life. If organs are genetically similar (body of a brother) (4.9) the odds of success are greater, but this seldom occurs. The application of immunosuppressive drugs can cause nephrotoxicity and / or hepatotoxic while medication changes tend to increase the percentage of rejection (4,5,12). Transfusion of blood from the donor could dampen the immune response to the graft, but there may be other diseases (hepatitis, AIDS, etc.).. The LMO associated with treatment of rejection depends on the response to medication and the time available.
Receiver Infections.
infections in immunocompromised individuals are common and can become severe being one of the most common causes of death in heart transplant recipients. This requires the application of broad spectrum antibiotics and continuous monitoring (4).
donor organ infections.
Under certain conditions, infections may own the donor organ, which is fighting administering medications to the receiver (4).
patient care and controls.
transplants require much expertise to give continuous attention to the patient, surgeons, cardiologists, pathologists, infectious disease, nursing (4). During all stages the patient receives large amounts of drugs and is permanently controlled for infection and rejection (4,6,11,16). The application of many drugs at all stages, including antagonistic drugs can produce unwanted side effects. Hospitals must have the necessary control equipment, intensive care units and transplant and ability to maintain the sterile barrier. The surgical work and health care, intensive surveillance and long periods of hospitalization and recovery make the costs are high (4). Because of the complexity of steps required is difficult to partial improvements of current techniques may lower costs. The LMO limited costs associated with every aspect referred to transplantation. LMO
The total depends on the LMO each intervening stage. It is found that cold preservation techniques have reached LMO, which is far from the desired result, then, does not make sense to keep developing new improvements on the cooling techniques and emphasizes the need to incorporate, Transcendent Conceptual Changes ( CST). In studies
uncertainties were detected among specialists, confirming once again the desirability of incorporating CCT : (i) for some current storage is correct, but others call for greater storage times (17), (ii) justified the use of techniques based on the cold, but it was found that the bodies are recovered better at higher temperatures (18 ), (iii) are changes with huge machines unworkable, regardless of advances in miniaturization, microelectronics and computer . Known
the need arise CST different solutions and analyze repeatedly applying the concepts postulated. The author proposes the hypothesis that the bodies remain to be preserved operating in normothermia: verifying this solution theory was proved that the problems go away and additional benefits.
THEORETICAL CHARACTERISTICS OF STORAGE DEVICE Normothermic
Application of normothermic techniques are based on the development of a Conservation Device Normothermic. The purpose of the device is to simulate the natural environment of the body and enable the flow of blood and other fluids (5). The ultimate goal is to make the body not detect differences between the donor's body (operating normal) y el Dispositivo. Aunque cada tipo de órgano necesitará un Dispositivo distinto, existirán características comunes.
En forma esquemática, el Dispositivo contaría con los elementos y las características siguientes: alojamiento para el órgano; mantenimiento del órgano en la oscuridad para evitar efectos indeseados de la luz (fotólisis, fotomagnetismo, fotocromogenicidad) (12); regulador de temperatura con sensores, para mantener la temperatura del conjunto igual a la temperatura normal del cuerpo; bombas que mantengan la presión adecuada de los fluidos y del órgano (quizás una sobrepresión sobre el órgano podría ayudar a su conservación); oxigenador (14); room for inspection, maintenance and addition of food and medications (anticoagulants, hormones), samples for analysis and replacement or replacement of blood volume; pacemaker to keep your heart rate and in other organs, strengthen pulsating rhythms of movement (4), detectors for monitoring, connecting elements to connect the donor first and then the receiver power from the network and from the battery or generator designed for this purpose.
Most items listed are already present (left ventricular assist device, rotating disk oxygenator, blood pump, etc.) and its size and weight can be modified to suit this new application (12.15).
Normothermic TECHNICAL PROPOSALS
The main idea is to get the organ to be transplanted to make a smooth transition from extraction (the donor) to its implementation (the receiver). If during this transition, the body would continue to function normally reduce their injuries and maintain their energy reserves within reasonable limits, without external inputs or basic needs (4.13). Should also eliminate the trauma that could damage the structure of the organ or unbalance operation. The movement must be continuous and should be kept roughly constant temperature and operating parameters of each organ, eg, adjust the heart rate by pacemaker and maintain the pressure gradient between the atria and ventricles (14).
normothermic techniques make possible the existence of "organ banks" permanently available for patients in need (10) and perhaps would not be used over the hopeless waiting lists. The illicit trafficking of organs and would not be a lucrative business, so this issue no longer worry.
With the body functioning normally within an environment that simulates their habitat, the shelf will reach new levels. The total suppression of ischemia-related damage and eliminate limit the application of compensatory drugs. With more time, provide the legal proceedings.
patient's adaptation to the new body will be carried out as previously unknown aspects before attempting a transplant within the Conservation Device: the rejection problems would occur in the body instead of suffering the patient-recipient. Graft infections (4) shall be treated within the device without affecting the future receiver.
The advantages and future possibilities opened up by this new concept are huge: it could be significantly reduced off time recipient's immune system and perhaps the studies and experiences could make unnecessary such deactivation. By having the body within a manageable and controllable enclosure could be made experiences trying to find the limits of their immune barrier: molecular perhaps disrupting his balance pressures and / or temperature and / or drugs while making the recipient's blood flowing through it, could mimic ("reset?) parameters organ to the patient-receptor ... then for the recipient's immune system would not be surprising graft ... It is also applied to the body of gene therapy to prevent rejection without any risk to the patient (even if you use animal organs).
lessened the severity of infection and quantity, the side effects and drug application periods of hospitalization and recovery. As the number of receptors (terminal or not) have access to organ transplantation to survive or to improve their quality of life (19,20), would be a gradual reduction of costs.
The concept of conservation device is applicable to any body that can be transplanted. For example, biliary atresia in children can be cured with liver transplant, but no suitable donor age: the solution is the reduction of the liver, separating a compatible adult liver in 2 or more fractions and using more than one transplant (4.12) (the device would allow its conservation).
For years, there are experimenting with xenografts (4,5,9,12). Using Conservation Device facilitate checks and studies to refine this technique. In the future, artificial organs (5) could be developed be adapted to each user within the Conservation Device.
donor selection.
be less demanding and that increasing the retention period will be time to cure organ dysfunction, studies of crossmatch, etc. Be used less restrictive criteria than today, including older donors and even dying from a disease that affects the body directly and definitively. After the declaration of death (4) and where possible, will continue using the systems of life support to preserve the functioning of the organs to be transplanted. It will be quickly incorporated each organ to be transplanted within the corresponding device Conservation. Which organs can be maintained for long periods will encourage the enactment of laws regulating their production, which will enable organ there is a stock capable of meeting the demands.
organ ablation.
Before organ ablation device will be connected to the Conservation (4) forcing its normal steady operation. Fluid will be circulated through the device and depending on the state of the organ will be added for medicine and all elements that can improve the blood donor. When the body reaches its normal operating range of the device due to the contribution of Conservation, will proceed to ablation and is conveniently accommodated within the device.
organ Conservation Conservation Device Normothermic.
With the organ within the device and controls will be relevant and applied studies of medications that the body needs. Could be preserved donor blood, although the use of substitutes would have some advantages: non-toxic, well tolerated, easy to maintain and do not transmit diseases (easy to sterilize). Will keep the body normal operation within the device so far to adapt to a patient-receptor.
Adaptation of organ recipients. It
replace donor blood substitutes in part by the patient's blood-receptor (exchange transfusion) (12,21). Allowed to circulate long enough to allow adaptation of the body and blood of the recipient will add more to completely replace the original liquids. State should be monitored for signs of organ rejection. For brief periods, you could disable the body's immune system and is at this stage which would make maneuvers designed to match the immunological parameters of the organ to the patient-recipient. The functioning of the organ with the recipient's blood should be maintained to achieve stability, since when we will try to transplant.
Implementation of the organ.
are connected in parallel (4) the donor organ with the organ to replace the device without disconnecting Conservation. The link should be maintained to verify that there is no irreversible acute rejection.
REFERENCES
- Limit Postulate Maximum Optimization (LMO ) : logical-mathematical procedure.
- Crick F: What Mad Pursuit. Tusquets Editores, Barcelona, \u200b\u200b1989, pg. 85.
- ibid 2., Pg. 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 Transplantation in Argentina and worldwide. Argentina Federation of Cardiology 4:281-285, 1991.
- Favaloro RR, Perrone SV, CV Gómez et al: Cardiopulmonary Transplantation. Argentina Federation of Cardiology 4:479, 1993.
- Vargas FJ, Lopez R, Diaz S et al: Pediatric Heart Transplantation in Argentina. Argentina Federation of Cardiology 4:492, 1993.
- ibid 7: First Pediatric Cardiopulmonary Transplantation in Argentina. Argentina Federation of Cardiology 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. Clin Transplantation 5: 467-474, 1991.
- Favaloro RR, Perrone SV, Comignani P et al: Trasplante Cardíaco. Federación Argentina de Cardiología 4:479, 1993.
- Dorland's Illustrated Medical Dictionary. EMALSA Interamericana/McGRAW- HILL, Madrid, 1988, 9° ed.
- 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 Preservation. Philadelphia Saunders, 1989.
- Scientific Tables, CIBA-GEIGY S.A., Basilea, Suiza, 1973; pág.645.
- Southard JH and Belzer FO: Principles of Organ Transplantation, Cap.10, Organ Preservation. Philadelphia Saunders, 1989, pág. 200.
- Minters J, Flameng W & Dyszkiewics: Transplant Int 1:19-25, 1988.
- Dantur J, Barico L, Marañón R et to: Cardiac Surgery at the 8 th and 9 th decade of life, XIV National Congress of Cardiology. Argentina Federation of Cardiology TL-21, P-21, 1994.
- Ficarra A, Caramutti E, Tomasini M, Leone L: Cardiac Surgery in Patients Over 75 Years, XIV National Congress of Cardiology. Argentina Federation of Cardiology TL-22, P-22, 1994. 21. Moullec J: Les Groupes Sanguins. Presses Universitaires, Paris, 1964.
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