THE ASYSTOLIC, OR NON-HEARTBEATING, DONOR (1997)

Kidney transplantation has become the victim of its own success: the improvement in quality of life after transplantation is-compared with dialysis-so impressive that most patients on dialysis ask for a transplant. This is illustrated by those who have lost their first graft and who nearly all ask to be placed on the waiting list again. In The Netherlands, 25% of the renal patients on the waiting list await a retransplant. In other fields of medicine, e.g., coronary bypass surgery, supply and demand are controlled by financial budgets. However, even with an unlimited budget for kidney transplantation, the number of transplants will still depend on the results of the procurement programs. The discrepancy between demand and supply has forced the exploration of other sources for kidneys. Programs for transplantation between spouses and programs for double transplants of kidneys from elderly cadaver donors have been developed; however, such programs will not slove the shortage. Only a new and innovative approach can solve the problem of shortage, and in our opinion the solution is the use of the asystolic donor. DEFINITION The term asystolic donor is quite specific for Great Britain, while in other parts of the world one speaks of a non-heartbeating (NHB*) donor. Both terms illustrate the condition wherein the organs are procured: the heart, and thus the circulation, of the donor has come to a standstill; this is in contrast to the heartbeating (HB) donor, in whom circulation is maintained until the last minute. Another option is to define the two different types of donors by the criteria whereupon death is diagnosed: heartbeating is a donor in whom death is based on brain criteria, whereas in the NHB donor death is based on heart criteria. In the past decades, extensive discussion has resulted in a well-defined definition and in methods to diagnose brain death. This is-in light of organ donation-not the case for death on heart criteria. The initiative for such a definition might find its start in the transplant world, as was the case for brain death. The concept of brain death has been defined by neurologists, whereas heart death has to be defined by cardiologists, anesthesiologists, and others involved in resuscitation. HISTORY The NHB donor is not new. Before the concept of brain death was established, transplant programs had to rely on cardiac arrest before they could procure the organs. We now know that results were reasonable, although a high percentage of delayed function in kidney transplantation resulted and the nonrenal organs from these donors were not suitable for transplantation. In those days, kidneys were perfused in preservation machines and efforts were made to predict transplant outcome during preservation (1-3). With the acceptance of the brain-death concept, the interest in donors after cardiac arrest declined. It is now the appropriate time in light of the organ shortage to revitalize this category of donors. TECHNIQUE The crucial point of the asystolic donor is that there is no circulation to the organs for a certain period. It is evident that this period has to be as short as possible; therefore, NHB donation is always happening in an emergency setting. From the moment of cardiac arrest, the organs start to decay. This decay cannot be stopped, but it can at least be reduced by cooling. This cooling could be total body cooling, as can be done with the help of a heart-lung machine (4), or the more popular, so-called “in situ cooling,” with the double-balloon, triple-lumen (DBTL) catheter, developed by Garcia-Rinaldi and Lefrak (5)(Fig. 1). In situ cooling has the advantage of being simple and effective, while total body cooling requires extensive technical setup. The DBTL catheter can be introduced in the emergency room, the intensive care unit, or at the ward. Any cooling method requires asepsis. In situ cooling is performed through a cutdown at the femoral vessels. The DBTL catheter is introduced into the femoral artery. Both balloons are moved up above the bifurcation of the aorta. The caudal balloon is then inflated, and the catheter is withdrawn until the caudal balloon hooks at the bifurcation of the aorta. At that point, the cranial balloon is inflated so that part of the aorta is isolated where the arteries of the kidneys spring off. A radio-opaque solution can be used to fill the balloons so that the position of the balloons can be checked by a flat abdominal x-ray. The cold (4°C) preservation solution flows through the third lumen of the catheter into the kidneys and the other visceral organs. The temperature of the kidneys will be reduced to about 15°C, and nearly all of the blood can be washed out. For outflow, a Foley catheter is introduced in the femoral vein. We use up to 15 L of a preservation solution (6). University of Wisconsin solution (7) is the best solution to use, but this is-in the volume used very expensive. We use histidine-tryptophan-ketoglutarate (HTK) (8) because it comes in 5-L containers and is cheaper. We have improved the DBTL catheter (Fig. 2), although the principle has not been changed. The improvements are: (a) the material is strong enough to withstand sharp clarifications inside the donor vessels, (b) the condition of the inside balloons can be checked by the small outside balloons at the filling tap, and (c) mark indicates how far the catheter has to be introduced into an adult. THE “10 MINUTES” RULE At the first international workshop on NHB donation at Maastricht in March 1995, extensive discussion (9) ensued on the issue when is the NHB donor dead and when is the correct moment to introduce the cooling catheter? One has to respect the so-called “dead donor” rule (10, 11), i.e., donors have to be dead when their organs are removed. The University of Pittsburgh Medical Center protocol (12) declares death 2 min after cardiopulmonary function has ceased. Arnold and Youngner (9) question the irreversibility of cardiac arrest after the 2 min and wonder whether all neurologic functions have ceased at that moment. At the Workshop in Maastricht (13) it was decided to end the discussion on the issue of when is the patient certainly dead by introducing a period of 10 min without perfusion of the brain before either (re)starting cardiac massage and artificial ventilation or introducing the cooling device. Basically, in these 10 min the potential donor is not touched by anyone from the treatment team or the transplant team. This period marks the transition from being a patient to being a dead person. A separation of the caregivers and the transplant team is self-evident. These 10 min add to the ischemic damage to the organs, but kidneys will be able to sustain this, although other organs, e.g., the liver, will become unsuitable for transplantation. These 10 min do not answer all the ethical questions concerning NHB donation. There remains the question of when to discontinue resuscitation in a dying patient. Here guidelines should be developed by the nontransplant medical field. Whether the cooling device can be introduced before or only after family consent is another point of dispute (9). In countries with “presumed consent” (opting-out) legislation, there seems to be no problem with prompt introduction of the DBTL catheter. In countries with opting-in legislation, one has to bridge the time from cardiac arrest plus the 10 min of “no touch” until the arrival and consent of the family. How should one bridge that period: cardiac massage and artificial ventilation or simply no efforts to circulate blood through the kidneys? The best solution would be to legislate the introduction of the DBTL catheter after cardiac arrest plus the 10 min of “no touch” during the period before arrival and consent of the family (14). CRITERIA What is the acceptable warm ischemia time in an NHB donor? This is not a simple question. Of importance is the quality of the circulation and oxygenation in the agonal period. Twelve hours of hypotension without urine output preceding the cardiac arrest is unfavorable, although the effect in a young patient is different than that in an older patient. Cardiopulmonary resuscitation can be effective. but there is no information on flow and perfusion of the kidneys. Very seldom is there urine output. Kidneys can stand 30-45 min of cardiac arrest. When it looks as if cardiopulmonary resuscitation would be very effective we tend to extend this time period another 60 min. For scientific comparison of data on warm ischemia in NHB donors, standardized definitions and uniform application of these definitions are needed. CATEGORIES Four categories of NHB donors can be identified (15). This division into categories makes sense because there are different legislative, ethical, and viability aspects for each category. Categories are listed in Table 1. There is hardly any experience with donors of category 1 due to logistics and questions about the viability of the kidneys. Category 2 is the main source of NHB donors. This category includes patient with myocardial infarction and cerebral bleeding and trauma victims. Category 3 comprises patients for whom life support has been withdrawn, as in a ventilator switch-off procedure. The 10-min, no-touch period is particularly relevant in categories 2 and 3. Category 4 has been introduced to remind doctors of the possibility of a switch to an NHB procedure when a HB procedure is complicated by an irreversible cardiac arrest. RESULTS The short- and long-term outcome of transplantation of kidneys from NHB donors is rather good, and thus encouraging. We have retrospectively studied (16) the outcome of 57 kidneys from NHB donors compared with a double number of matched HB controls. As could be expected, the delayed function rate was higher (60% vs. 35%) and the number of primary never-functioning grafts was, although not significantly different, at the cost of the NHB donor kidneys. The long-term outcome of the NHB donor kidneys was equal to that of HB donor kidneys. Other programs, e.g., in Leicester (17), Zürich (18), Pittsburgh (19), Barcelona (Hospital Clinic) (20), and Hospital de Bellvitge (21), Warsaw (22), and Madrid (23), have reported similar or even better results (Zürich (18)). Two programs have reported rather poor results: Istanbul (Tip Fakültesi (24)), reported a high percentage of primary nonfunction (23%) and poor graft survival (40%) at 1 year, and King's College in London (25) reported 55% graft survival at 2 years. In the latter program, hospice-based deaths were included. These patients died under circumstances unfavorable for good viability of the organs. In our study (16), kidney function (serum creatinine and creatinine clearance) did not differ at 3, 6, and 12 months after transplantation between the NHB donor kidneys and the HB-matched controls. Nicholson (26) reports slightly less satisfactory outcome for NHB donor kidneys compared with HB kidneys. He relates this to common delayed function, which might have a detrimental effect on the outcome (27). HURDLES There are several hurdles to be overcome before worldwide acceptation and application of the concept of NHB donation. The first hurdle is the acceptance of death based on cardiac criteria by the medical profession and the lay public. Social acceptance of NHB donation is still in its youth. The second hurdle is legislation enabling the start of cooling shortly after death. After successful procurement, two main hurdles remain: the very high percentage of delayed graft function and the disappointing number of primary nonfunctioning grafts. All of the above is in regard to renal transplantation. It is very unlikely that with the “10 minutes” protocol other organs will be suitable for transplantation, mainly because substitution therapy after transplantation of these organs, such as dialysis in kidney transplantation, is not yet available. This delayed graft function can be attacked in several ways. The first is to adjust the immunosuppression, e.g., by withholding cyclosporine. Schlumpf et al. (18) and Varty et al. (28) replaced cyclosporine with antithymocyte globulin and OKT3, respectively, in order to avoid cyclosporine nephrotoxicity during the first days after transplantation. We have reintroduced machine preservation (MP) for NHB donor kidneys, based on literature and own experimental work. Feduska and Cecka (29) observed in HB kidneys a delayed function rate of 18.3% with MP, compared with 28.5% with cold storage (CS). Their series is very large (45,450 kidneys), and there is no reason to believe that what applies for HB kidneys will not apply for NHB kidneys. Matsuno et al. (30) preserved from the same NHB donor one kidney using CS, and the other using MP. Of the 16 donor pairs, the MP kidney showed earlier function than the CS-preserved kidneys. We (31) observed a better preservation of the renal microcirculatory integrity with MP versus CS in the ischemically damaged dog kidney. Light et al. (32) observed higher immediate function rates with kidneys of marginal donors stored with MP compared with “ideal” CS kidneys. Although Light confirms our finding (33) that MP can be cost-effective, MP was been abandoned in Europe many years ago because it had no obvious advantage over CS and it needed personnel, machinery, maintenance, etc. We expect to have another pro argument for MP in NHB donation. It offers the opportunity to reexplore viability testing, as was done in the 1970s, and this might be of great importance for the popularity of NHB donation. VIABILITY TESTING NHB donor kidneys suffer from warm ischemia in the donor. The extent of this warm ischemic damage is difficult to determine based on clinical data, e.g., length of warm ischemia, effectiveness of the flush-out, and cooling. There is a need for an objective test that quantitates the ischemic damage. Several approaches have been developed, including energy charge (nucleotides), enzyme release, and functional studies. Adenine triphosphate and total adenine nucleotide cannot predict organ viability in organs damaged by ischemia (34). Phosphorus-31 magnetic resonance spectroscopy enables noninvasive measurement of phosphorus monoesters and in organic phosphorus, and the ratio correlates with warm and cold ischemia in rat and dog kidneys (35). There is no experience with human kidneys that have suffered warm ischemia. Yin and Terasaki (36) tested the activity of the mitochondrial reduction-oxydation enzymes in animal kidneys with the reduction of tetrazolium salts to formazan in a kidney biopsy. We could not confirm their results in human kidneys. Release of lysosomal enzymes, e.g., lactate dehydrogenase, has been studied extensively studied, but there is no correlation with warm ischemia (37). The lysosomal enzyme of the proximal tubulus cell glutathione S-transferase was able (38) to predict outcome of human kidney function before transplantation. A more specific enzyme of the proximal tubulus cell is α-glutathione S-transferase, and we found a correlation with warm ischemia and the release of this enzyme in the perfusate of the preservation machine. Research is ongoing. Monitoring of electrolyte activities at the organ surface with ion-selective electrodes correlates pretransplant K+ to posttransplant function (39). The kidneys in this experiment had not sustained warm ischemia. Measuring vascular resistance of the ischemic kidney in the preservation machine is helpful, but it does not provide an objective parameter (40). We studied flow and perfusion defects with radioactive xenon-133 and technetium-labeled hexamethylpropyleneamine oxime during MP (31). The test has not yet been transferred to human kidneys. The outcome of a kidney transplant depends not only on donor factors, such as warm ischemia, preservation, etc., but also on recipient factors, such as state of immunization and cardiovascular status. This frustrates clinical research, unless one has very large figures wherein recipient causes of kidney failure are outnumbered. POTENTIAL AND YIELD OF NHB PROGRAMS The effectiveness of NHB programs is lower than that of HB donation. More kidneys are discarded for reasons of damage, poor flush-out, and uncertain sterility (41). Nicholson (42) has found that the yield of an NHB program is rather low due to the above-mentioned reasons. In the past few years, we have 40% more kidneys through the extension of our program with an NHB donor program. Our refusal rate is about the same (35%) as in HB donation, in spite of the time pressure. We have calculated for our area a potential increase in kidneys for transplantation of 2-4.5 times. If realized in The Netherlands on a nationwide basis, the shortage of kidneys would be a thing of the past. CONCLUSIONS Worldwide introduction and application of an NHB donor program has the potential to solve the problem of shortage, at least for kidneys. Important steps are: (a) to define when cardiopulmonary resuscitation in a patient can be discontinued and when the situation of NHB donation can be considered, (b) to legislate the introduction of the cooling device, and (c), last but not least, to develop a viability test for kidneys from NHB donors. For this test, we consider MP a prerequisite. Establishment of regional centers for MP of kidneys might be a good model. Every transplant program should consider the start of an NHB program in consultation with ethical and legal authorities and in collaboration with a regional MP test program.Figure 1: Original drawing from Garcia-Rinaldi et al. (5) demonstrating the use of the DBTL catheter (used with permission).Figure 2: Improved DBTL catheter with small balloons at the filling tip and a mark for distance of introduction (arrow).