4
The Modern Non-Heart-Beating Donor

The Controlled NHBD

More than 50,000 patients are on the waiting list for organs in this country (UNOS, 1997), awaiting a lifesaving treatment for which personnel, facilities, and for the insured, funds are not limiting. The waiting list not only is growing rapidly but likely is a significant undercount, omitting many, as noted, who withdraw or who are discouraged by the long waits and uncertain prospects. Waiting list deaths are also mounting, and they too may be underestimated because deaths of those removed from the list as they deteriorate beyond transplantability are not counted as waiting list deaths. In reaction to the increasing need for organs, transplant programs have begun to revisit the traditional sources of donors, focusing on the controlled category of NHBDs, although some, such as the University of Wisconsin at Madison, have always had an active NHBD program. The Pittsburgh "Policy for the Management of Terminally Ill Patients Who May Become Organ Donors After Death" (Arnold, 1995), devised after extensive local review and subject to wide commentary from the ethics and medical community after issuance, was emblematic of this return to former sources. Some of the issues raised by the Pittsburgh protocol, examined by the medical and ethics communities and reported in depth in the medical and ethics literature, have not been conclusively resolved and are taken up again in this report.

As noted earlier, the NHBD is a donor whose death is defined by "irreversible cessation of circulatory and respiratory functions" as opposed to "irreversible cessation of all functions of the entire brain, including the brainstem" (Uniform Determination of Death Act, 12 Uniform Laws Annotated 320 [1990 Suppl.]). Organs recovered from such a donor cannot be ideally suited for transplantation because cardiopulmonary death means that organs will not continue



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--> 4 The Modern Non-Heart-Beating Donor The Controlled NHBD More than 50,000 patients are on the waiting list for organs in this country (UNOS, 1997), awaiting a lifesaving treatment for which personnel, facilities, and for the insured, funds are not limiting. The waiting list not only is growing rapidly but likely is a significant undercount, omitting many, as noted, who withdraw or who are discouraged by the long waits and uncertain prospects. Waiting list deaths are also mounting, and they too may be underestimated because deaths of those removed from the list as they deteriorate beyond transplantability are not counted as waiting list deaths. In reaction to the increasing need for organs, transplant programs have begun to revisit the traditional sources of donors, focusing on the controlled category of NHBDs, although some, such as the University of Wisconsin at Madison, have always had an active NHBD program. The Pittsburgh "Policy for the Management of Terminally Ill Patients Who May Become Organ Donors After Death" (Arnold, 1995), devised after extensive local review and subject to wide commentary from the ethics and medical community after issuance, was emblematic of this return to former sources. Some of the issues raised by the Pittsburgh protocol, examined by the medical and ethics communities and reported in depth in the medical and ethics literature, have not been conclusively resolved and are taken up again in this report. As noted earlier, the NHBD is a donor whose death is defined by "irreversible cessation of circulatory and respiratory functions" as opposed to "irreversible cessation of all functions of the entire brain, including the brainstem" (Uniform Determination of Death Act, 12 Uniform Laws Annotated 320 [1990 Suppl.]). Organs recovered from such a donor cannot be ideally suited for transplantation because cardiopulmonary death means that organs will not continue

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--> to receive oxygenated blood up to the moment of removal from the donor. Before the establishment of the whole-brain determination of death, NHBDs were the only kind of cadaver donor, but the essentially total phasing out of the NHBD thereafter is convincing testimony to the preferability of organs from brain-dead (heart-beating) donors. In fact, in the transplantation literature, discussions of a return to the practice of procuring organs from NHBDs almost invariably begin by explaining that the shortage of organs and the intense pressure to increase supply are driving consideration of organs retrieved from NHBDs (Bos, 1995). The modern, controlled NHBD differs in a number of ways from the historical, uncontrolled NHBD. Over the past several decades, court cases, ethical debates, public reporting, major religious pronouncements, and undoubtedly the mere passage of time have allowed better public understanding and acceptance and an alleviation of concerns about withdrawal of life-sustaining treatment from certain patients (Banks, 1995; Council on Scientific Affairs and Council on Ethical and Judicial Affairs of the American Medical Association, 1990; Emanuel, 1988; Kennedy Institute of Ethics Journal, 1993; President's Commission, 1983). These patients are either competent with intolerable quality of life or incompetent, but not brain dead, because of severe, generally neurological, illness or injury with an extremely poor prognosis as to survival or any meaningful functional status. A significant number of patients, therefore, can be identified for whom, after proper safeguards and with informed consent from the competent patient or from surrogate decision maker(s) for the incompetent patient, life-sustaining treatment may be discontinued. These patients who are being maintained on artificial ventilation or, occasionally, circulatory assistance will suffer irreversible cessation of circulatory and respiratory functions within a short interval after withdrawal of support. Death will almost always occur soon enough after withdrawal of support to allow the removal of viable organs for transplantation. This kind of NHBD—the controlled NHBD—is the one that most closely simulates the ideal conditions for organ recovery which exist with organs procured from heart-beating cadaver donors; that is, it is the donor with the shortest time between absence of circulation and removal of organs, and it is the most common kind of NHBD in the United States. These donors are controlled because the timing and thus the process of donation are controlled through the timing of life support. The time interval for organ recovery starts with the withdrawal of life support and ends usually within 1 or 2 hours. Under certain circumstances and in some programs a different interval may be selected if the patient dies within that time. If the patient's death after withdrawal of support is delayed beyond an hour or two, a determination is often made that organ viability has suffered too much during the dying process to warrant transplantation.

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--> Box 4.1 Maastricht Categories for Non-Heart-Beating Donors I. Dead on arrival. II. Unsuccessful resuscitation. III. Awaiting cardiac death. IV. Cardiac death in a brain-dead donor.   SOURCE: Kootstra, 1995. The Uncontrolled NHBD There are a number of other categories of NHBDs, referred to as uncontrolled. Some, primarily Europeans, separate NHBDs into numbered categories (See Box 4.1) including three uncontrolled donor categories (Maastricht categories I, II, and IV) and one controlled donor category (Maastricht III) (Kootstra, 1995). Uncontrolled NHBDs include those whose hearts have stopped shortly before arrival at the hospital (category I), those who suffer cardiopulmonary arrest in the hospital and cannot be resuscitated (category II), and those who, having been determined brain dead, suffer unexpected cardiac arrest (category IV). Uncontrolled donors make up the bulk of many European programs. Some American programs consider both categories III and IV as controlled (see chapter 5, J. Light, personal communication, 1997). Kidneys, livers, pancreases, and lungs can be recovered from controlled NHBDs (D'Alessandro et al., 1995a,b). Recovery of other than kidneys is problematic from uncontrolled donors (Kootstra, 1997) but may be possible with early organ perfusion using the appropriate cold solutions. Often this intervention must be started so quickly after death that circumstances do not allow consent to be obtained, which poses a problem in the United States. The contribution of kidneys retrieved from uncontrolled NHBDs to the kidney supply is fortunate because this is the organ most in demand (D'Alessandro et al., 1995a; Kootstra, 1997). On the other hand, in terms of addressing the supply shortage, it is unfortunate that uncontrolled donors with their limitations are potentially the largest category of donors (Light et al., 1996; Nicholson, 1996). Furthermore, in all types of NHBDs, organ recovery and transplantation rates are lower than in heart-beating donors, as previously noted. Of the various types of NHBDs, it is clear that the uncontrolled donor has the greatest interval between cessation of circulatory function and cold perfusion or removal of organs. During this time, which in some programs may exceed an hour, there is deterioration of all organs. In the case of kidneys, this means delay of graft function in as many as 60% (Kootstra, 1997), 74%

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--> (Hoshinaga et al., 1995), or even 100% of cases (Nicholson et al., 1997; Varty et al., 1994). This compares to the 22% to 26% reported achievable in controlled NHBD programs (A.M. D'Alessandro, personal communication, July 21, 1997; Orloff et al., 1994). The best figures are in brain-dead (heart-beating) or living donors, averaging around 20%, although some programs using machine perfusion achieve 7% to 8% (A. M. D'Alessandro, personal communication, July 21, 1997). Delayed graft function does not prohibit kidney transplantation because function can be replaced by dialysis until recovery. Other organs are less tolerant of circulatory arrest and without artificial functional substitutes are said to be effectively ruled out (Kootstra, 1997), although this situation may change. Delayed kidney function is also associated with decreased long-term (3-year) graft survival (UNOS, 1997, Report of Center Specific Graft and Survival Rates) and with more frequent acute rejection reactions (Wijnen et al., 1995). Ultimately, this combination of delayed function and acute rejection is also associated with decreased long-term graft survival (Cosio et al., 1997; Troppmann et al., 1996). For all kinds of NHBDs, these conditions have generated intense pressure to approach the favorable conditions of the brain-dead (heart-beating) and living donor. This requires the following, to the extent possible: a precise prediction of the timing of, and a short interval to, death; a prompt determination of death and organ retrieval; a rapid initiation of cold preservation; and an acceptance of a full array of interventions that might enhance organ viability and stabilize the patient for donation. These are the kinds of pressures that have justified "presumed consent" laws in many countries, which authorize, unless there is notice to the contrary, nonconsensual organ perfusion or even in some cases organ removal while awaiting consent for donation (Veatch and Pitt, 1995). In the United States, the District of Columbia has a law that allows perfusion and cooling without consent and a successful program that utilizes this statutory authority to procure uncontrolled NHBDs (87 Stat. 813:D.C. Code § 1-233(c) (1)). Virginia and Florida also have such a law, although in Florida no nonconsensual cooling is done despite statutory authority (Reiner, 1997). A few states have proposed but not enacted similar laws—the Regional Organ Bank of Illinois practiced nonconsensual cooling for a short time (UNOS, 1996)—and a number of observers have urged a policy of initiating cooling without consent (Anaise and Rapaport, 1993). Current Status Of The NHBD In Transplantation The exploration of the modern NHBD, in an attempt to redress the imbalance between supply and demand, began in the early 1990s, and was enhanced by the far-reaching discussion and analysis of the 1992 Pittsburgh protocol. Actual transplantation using controlled NHBDs in the United States started as a small effort and has remained so. Figures cited in one report (DeVita, 1995)

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--> were 20 total NHBDs in 1992 and 45 total NHBDs, of which 34 were controlled, in 1993. UNOS data (M. Ellison, personal communication, June 27, 1997) in Tables 4.1A and 4.1B suggest a baseline of a small number of uncontrolled NHBDs. TABLE 4.1A. Non-Heart-Beating Donors Recovered in the United States: 1993–1996   No. of Donors Percentage of Organ-Specific Donors Year Recovered Kidney Liver Heart Lung Pancreas 1993 43 100.0 37.2 4.7 9.3 19.4 1994 59 98.3 39.0 8.5 10.2 13.6 1995 44 100.0 22.7 0.0 4.5 4.5 1996 65 96.9 24.6 0.0 1.5 10.8 1993–1996, Overall 211 98.6 30.8 3.3 6.1 11.4   SOURCE: Based on UNOS OPTN/Scientific Registry data as of June 14, 1997. Data subject to change based on future data submissions. TABLE 4.1B. Number of Transplants Performed with Non-Heart-Beating Donors: 1993–1996 controlled vs. Not Controlled     Year of Transplant Organ Category 1993 1994 1995 1996 1993–1996, Overall Kidney Controlled 0 21 48 67 136   Not controlled 68 63 23 28 182 Liver Controlled 0 5 3 9 17   Not controlled 9 7 3 2 21 Heart Controlled 0 0 0 0 0   Not controlled 0 2 0 0 2 Pancreas Controlled 0 0 1 6 7   Not controlled 5 0 0 1 6 Lung Controlled 0 0 0 2 2   Not controlled 1 0 0 0 1 Total Controlled 0 26 52 84 162   Not controlled 83 72 26 31 212 Overall   83 98 78 115 374   SOURCE: Based on UNOS OPTN/Scientific Registry data as of June 14, 1997. Data subject to change based on future data submissions. Given the lack of data and the reporting of controlled and uncontrolled numbers together in 1993 and part of 1994 (reported as "not controlled"), little can be concluded about uncontrolled NHBD trends, but the numbers appear fairly stable. The small number of controlled NHBD transplants may be slowly

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--> increasing, although here too it is early to draw firm conclusions. The overwhelming majority of these NHBD transplants (85%) were kidneys, as is the case in other countries; and low transplant or donor rates seem consistent over time. Roughly half of transplant programs (120) and organ procurement organizations (36) recovered organs from at least one NHBD during 1993–1996. TABLE 4.2. Kaplan–Meier Graft Survival Rates for Transplants Performed 1993–1995, Controlled vs. Not Controlled for Non-Heart-Beating Donors Cadaveric Organ Non-Heart-Beating Donor Controlleda Months Post-transplant n Survival Rateb Standard Error Kidney Yes Yes 6 63 88.1 4.0       12 45 86.4 4.0     No 6 149 81.6 3.1       12 138 78.9 3.3       18 123 78.1 3.4       24 106 76.3 3.5   No   6 23,262 87.6 0.2       12 19,877 85.0 0.2       18 16,091 82.8 0.3       24 13,123 80.7 0.3 Liver Yes Yes 6 7 — —       12 7 — —       18 6 — —       24 6 — —     No 6 18 46.8 11.6       12 17 40.9 11.5       18 16 32.7 11.8       24 15 32.7 11.8   No   6 9,551 79.0 0.4       12 7,823 75.2 0.4       18 6,339 72.1 0.5       24 5,311 70.0 0.5 a Data on controlled versus not controlled were not collected prior to April 1994. b "—" means that a survival rate could not be computed because n at risk is less than 10. SOURCE: Based on UNOS OPTN/Scientific Registry data as of June 14, 1997. Data subject to correction based on future data submission or correction. The results of transplantation reported since 1994, the first year that UNOS began keeping separate statistics on controlled and uncontrolled NHBDs, are shown in Table 4.2, which, because of small numbers, includes only kidney and liver data. The same data are displayed in Table 4.3, except that results of transplants using organs from NHBDs are reported in total rather than separately as controlled and uncontrolled. These data are consistent with the conclusion that transplants using kidneys from NHBDs (primarily controlled NHBDs) provide

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--> results close to or almost as good as brain-dead (heart-beating) donors. In Table 4.3 total results of liver transplants using NHBD livers are dramatically worse than liver heart-beating donor results, and since uncontrolled NHBD liver results in Table 4.2 are slightly better than total results, a small group of more successful controlled donor grafts is not hidden in the total. Because of insufficient numbers, these data are preliminary indications only, but they tend to support the promise of NHBD kidney transplantation, perhaps with slightly reduced graft survivals; to confirm that fewer organs per donor are recovered from NHBDs, and these are mostly kidneys; and to suggest that further improvements in liver transplantation with NHBD livers could, and probably will be achieved. They are also consistent with reports from elsewhere, except that controlled NHBD liver transplants, reported separately, have much higher success rates (Casavilla et al., 1995a,b; D'Alessandro et al., 1995a,b). A separate analysis using UNOS data of 204 kidney transplants supports these conclusions (Cho et al., unpublished work, 1997). TABLE 4.3. Kaplan-Meier Graft Survival Rates for Transplants Performed 1993-1995 Cadaveric Organ Non-Heart-Beating Donor Months Post-transplant n Survival Rate Standard Error Kidney Yes 6 212 83.6 2.5     12 183 81.2 2.7     18 149 79.8 2.8     24 125 78.3 2.9   No 6 23,262 87.6 0.2     12 19,877 85.0 0.2     18 16,091 82.8 0.3     24 13,123 80.7 0.3 Liver Yes 6 25 43.7 9.7     12 24 39.3 9.6     18 22 26.2 9.9     24 21 26.2 9.9   No 6 9,551 79.0 0.4     12 7,823 75.2 0.4     18 6,339 72.1 0.5     24 5,311 70.0 0.5   SOURCE: Based on UNOS OPTN/Scientific Registry data as of June 14, 1997. Data subject to correction based on future data submission or correction. Reports from individual programs in this country and abroad comparing results of transplants using organs from controlled and uncontrolled NHBDs with brain-dead (heart-beating) or living donors have generally documented competitive 1-year kidney graft survivals but provided less information on longer-term

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--> function. Some longer-term results have been encouraging (Alvarez-Rodriguez et al., 1995; Schlumpf et al., 1996; Wijnen et al., 1995); whereas others are less so (Andrews et al., 1995; Nicholson, 1996; Nicholson et al., 1997; Phillips et al., 1994; Szostek et al., 1995; Valero et al., 1995). Rates of delayed kidney graft function have been high, particularly in transplants using organs from uncontrolled NHBDs, as noted earlier. These results should be compared both to results from the best types of donors and to the hazards and the economic and human costs endured by patients on the waiting list or by the set of patients who because of implicit rationing are not formally listed. Many observers have concluded that they support aggressive continued development and use of organs from NHBDs as a resource for kidney transplantation and, especially with controlled and perhaps with uncontrolled donors, for other organs as well. All this depends of course on the availability of reasonable numbers of such donors. The numbers of NHBD organ transplants in the United States cannot have had any significant effect in meeting demand to date. From 1993 to 1996, NHBDs made up around 1% of total cadaver donors, varying between 0.8% (1995) and 1.2% (1994, 1996) (M. Ellison, personal communication, June 27, 1997). Meanwhile, European programs (Kootstra and Daemen, 1995) have reported as much as a 40% expansion in cadaver donors (mostly uncontrolled NHBDs) (Daemen et al., 1996), and a 20% to 25% increase is routinely achieved or predicted (Nicholson et al., 1997; Wijnen et al., 1995). One large program in this country reports that 16 NHBDs (all controlled) comprised 12.3% of total cadaver donors (a 14% expansion) and 8.6% of transplanted organs during a 17-month interval in 1993 and 1994 (D'Alessandro et al., 1995b). A second program reports 26 NHBDs (12 controlled) during a 5.5-year period leading up to 1995 (Casavilla et al., 1995a). One U.S. source (Nathan et al., 1991) estimated that controlled NHBDs have the potential to increase cadaver donors by at least 25%. More expansive estimates have also been made for a more inclusive group of NHBDs: 25,000-26,000 NHBDs, 123 dmp (Nathan, 1997) as cited in Daemen et al. (1996), 2.3% of hospital deaths (Bart et al., 1981); the number of uncontrolled NHBDs being six times greater than the number of controlled NHBDs (Light et al., 1994). If the estimates are close to accurate, organs recovered from at least 1,000 controlled NHBDs could be added to the cadaver donor organ supply each year, and probably more. When added to potential increases in the supply of organs from living and heart-beating donors, this would have substantial impact. Yet at best, only 6% to 7% of this number is being reached. Significant realization of estimated uncontrolled NHBD potential would have an even greater effect. Of course, these estimates are speculative. In 1994, a survey showed that 20 of 66 OPOs (30%) had NHBD protocols; of the 66 OPOs, 25 had procured and 23 had transplanted organs from NHBDs (UNOS, 1994). In 1997, the Institute of Medicine (IOM) asked all (at that time)

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--> 63 OPOs to submit their NHBD protocols as part of the information gathered for this report. Information was collected from 100%. Some protocols under development were not submitted, but all final approved versions were obtained (see chapter 5). Slightly more than half of OPOs had protocols, although a larger proportion reported that they were actually recovering organs from such donors. Other OPOs had a number of reasons for not exploring recovery of organs from NHBDs, as described later. In fact, the majority of transplant programs served by OPOs do not perform transplants from NHBDs (M. Ellison, personal communication, June 27, 1997), and some programs limit their efforts to controlled donors, which also limits the amount of expansion that is possible (D'Alessandro, 1995a). Given a social consensus, there are a number of things that could improve the supply of organs relative to demand. Steps to improve the supply of organs from one category of donor often improve those of other categories as well. Steps that might be taken include the following: investments in improving rapid responsiveness of hospitals to identify potential donors, development and implementation of better public education and of better ways to get consent for donation, uniformly asking for consent, better support of donors (e.g., better early recognition and better initiation of life support and maintenance), wider acceptance of expanded donor criteria including emotionally related living donors, more organs retrieved per donor, research to improve organ use (e.g., screening methods for viability to enhance use of good organs and minimize use of organs that are not in good condition), increased research in general to improve transplantation success rates and reduce retransplantation, and continued experiments at the state ultimately, national level, (e.g., registries, required notification of hospital deaths to OPOs, or perhaps extension of required requests to potential category III NHBDs). This list should also include the following: expansion of the procurement of controlled and uncontrolled NHBDs, improved effectiveness of OPOs and OPO policy, and procedural readiness to access all categories of donors. This report also makes recommendations that could provide a more consistent, publicly acceptable nationwide NHBD effort, which could have a positive effect on donation rates. There are both scientific justification and historical precedent for expanding into the NHBD category, and a substantial increase* in donors seems quite possible as a result. Given the uncertain assumptions and the variable existing predictions involved, an estimate of the magnitude of the increase would be highly speculative. In view of the shortfall in organ supply and its human cost, however, *   As noted earlier, the size of any increase is speculative, but credible experts (Nathan, 1991) and transplanters (Kootstra, 1997) have estimated upward of 25% more cadaver donors. Safar (1988) has estimated that there are annually 250,000 acute, presenile, not incurably diseased cases of death in the United States in which resuscitation attempts might be justified. Recovery of organs from even a small fraction of these potential uncontrolled NHBDs would represent a substantial contribution.

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--> best efforts should be made to develop reasonable solutions. At the same time, there should be a realistic understanding of the limitations of the NHBD given current technology and procedures. Both the lower numbers of organs per donor (because of their deterioration in the body of the donor) and the condition of the organs that are recovered limit the benefits, and undoubtedly increase the costs of NHBDs relative to other categories of donors. There also seems to be considerable inertia in developing procurement policies, as well as uncertainty and anxiety about the proper policies and procedures to adopt. In some OPOs, there is opposition to NHBDs, and because some of this opposition is said to reflect public concerns, it could be difficult to change. Identification, discussion, and if possible, resolution of some of the outstanding issues concerning the proper ethical and medical management of these donors might help to overcome this uncertainty or opposition if they are indeed among the reasons for the very slow expansion of the NHBD pool.