B o ne M a rro w T ra n sp la n t Pa t i e n t s W i t h L i f e - Th r e a t e n i ng Org a n F a ilu re : Wh e n S h o u l d Tr e a t m e n t S t o p? By Amanda R. Perry, Michael M. Rivlin, and Anthony H. Goldstone Purpose: To discuss issues surrounding life support in bone marrow transplant (BMT) patients, issues that may determine how far we go to keep a deteriorating BMT patient alive—and when we stop trying. How can we define survival chance in BMT patients, and when should prolongation of life be deemed inappropriate? Who should make the decision to terminate support? And how should life support be terminated? Design: Prognostic factors that predict for almost certain nonsurvival have been identified in BMT patients with life-threatening organ failure. The concept of futility raises the question of how low the chance of survival must be before termination of life support is justified— but the concept is flawed, and the value judgments involved in decision making must also be considered. Then, once a decision is made, the manner of withhold-

ing or withdrawing life support is also open to discussion. Conclusion: Despite controversies, there are areas in which improvements to current practice might be considered. More data are required to determine survival chances of BMT patients with life-threatening organ failure. Greater attention might be devoted, in pretransplant counseling, to issues of intensive life support, with the patient’s own views being ascertained before transplantation. And, because technologic possibilities are now imposing fewer boundaries, the problem of finite resources may need to be readdressed, with treatment limits being set down before transplantation. J Clin Oncol 17:298-303. r by American Society of Clinical Oncology.

M

because of the young age of patients and because of the real possibility of cure if the patient can survive the transplantation. Further, unlike in so many situations, the possibility of life-threatening complications can be anticipated before the BMT procedure, so the views of patients can actually be taken into account in decisions to withdraw treatment. Finally, in the field of transplantation, the problem often goes beyond that of continuing life-support therapies and involves questioning of the value of more aggressive and expensive attempts to salvage lives that may in the end be unsalvageable. Thus, it seems appropriate to reconsider the management of BMT patients with life-threatening organ failure. Currently, there are often conflicting opinions with regard to the appropriateness of continuing therapy; facts are confused with value judgments, and the degree of intervention is often reduced nonsystematically, as a feeling of hopelessness gradually outweighs hope. Moreover, the argument that patients should be treated as far as is medically possible is stretched by the availability of more therapies, with technology putting fewer limits on treatment.

UCH IS INVESTED IN bone marrow transplantation, not only in resources but also in media and public sympathy and in hope by the patient, family, and physician. Yet mortality after bone marrow transplantation, particularly allogeneic transplantation, remains high. Most non-survivors end their lives in the hospital. Once lifethreatening organ failure develops, the outlook is truly bleak; frequently, single-organ failure becomes multiorgan failure, deterioration becomes relentless, and further prolongation of life may seem not only hopeless but inappropriate. Recognizing and managing such a situation, however, is not easy. A great deal has been written about terminating life support, but there are reasons why bone marrow transplant (BMT) patients should be given particular consideration. First, they represent a fairly homogeneous group in whom predictors of nonsurvival might be identifiable; indeed, there have been several recent attempts to define criteria for withdrawing life support in BMT patients. Second, the dilemmas surrounding bone marrow transplantation are more starkly emphasized than in other areas of medicine

From the Department of Haematology, University College London Hospitals, London; and Department of Philosophy, University of Leeds, Leeds, England. Submitted September 12, 1997; accepted September 23, 1998. Supported by the Leukaemia Research Fund. Address reprint requests to A.R. Perry, MRCP, Department of Academic Haematology, Institute of Cancer Research, Cotswold Rd, Sutton, Surrey SM2 5NG, England. r 1999 by American Society of Clinical Oncology. 0732-183X/99/1701-0298$3.00/0

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SURVIVAL IN BMT PATIENTS WITH LIFE-THREATENING COMPLICATIONS

A fundamental question is whether there are predictors of nonsurvival among BMT patients with life-threatening complications. The most common procedure-related cause of death in BMT patients is respiratory failure, and many patients die while undergoing mechanical ventilation. Several retrospective studies in large transplant centers have examined survival in mechanically ventilated BMT patients. Journal of Clinical Oncology, Vol 17, No 1 (January), 1999: pp 298-303

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For example, of a total of 653 BMT patients in one U.S. center, 191 (29%) were mechanically ventilated.1 Of these, 161 (84%) died while being ventilated or within hours of extubation, 18 (10%) survived a week, and only six patients (3%) survived 6 months. In particular, all patients older than 40 years of age died within 30 days of ventilation, and all patients who required ventilation in the first 90 days after transplantation died by day 100. Another study, from the Fred Hutchinson Cancer Research Centre in Seattle, WA, identified risk factors for nonsurvival by nested case-control analysis.2 Of 836 mechanically ventilated BMT patients, representing 24% of all BMT patients, 53 (6%) survived, although only 4% lived 6 months or longer. Three risk factors for nonsurvival were identified: lung injury (fraction of inspired oxygen ⬎ 0.6 or positive end-expiratory pressure ⬎ 5 cm H2O after the first 24 hours of ventilation), vasopressor use for more than 4 hours in any 24-hour period after ventilation, and hepatic and renal failure (bilirubin level ⬎ 68 mmol/L, creatinine level ⬎ 177 mmol/L sustained for 3 days). If two of these three risk factors were present, the chance of survival was estimated to be 1 in 476. Life-threatening conditions other than respiratory failure include grade 4 graft-versus-host disease and venoocclusive disease, in which outcome may also be extremely poor. Many of the identified predictors of death in BMT patients with life-threatening complications are listed in Table 1.1-7 There is clearly some disagreement regarding which factors predict nonsurvival, as well as a variation in mortality rates, although these are to some extent influenced by which groups are analyzed. Notably, patient and transplant-related characteristics (sex, diagnosis, type of graft, conditioning regimen, graft compatibility), with the excep-

tion of age, do not seem to be predictive of nonsurvival, whereas surrogate markers of multiorgan failure seem to be more predictive. There are obvious difficulties in translating findings to centers where ventilatory and other practices may differ, and there remains the possibility that medical advances will improve outcome in the future. Nonetheless, the results of these studies form a better evidence base at present than do anecdote and individual experience. FUTILITY

It may be possible, then, to define risk factors for a low chance of survival in BMT patients once life-threatening organ failure develops. A low chance of survival, however, is not the same as a futile situation.8,9 How do we define futility? According to the Appleton international guidelines on decisions to forego life-prolonging treatment,10,p.11 ‘‘a treatment that cannot reasonably be expected to achieve even its physiological objective is physiologically futile, and need not be offered or provided if requested.’’ This narrow definition of physiologic futility is relatively unhelpful in the context of a sick BMT patient. Individual treatment measures are often not physiologically futile; ventilation, hemodialysis, inotropic support, antimicrobials, cytokines, leukocyte therapy, and even solid-organ transplants may well have short-term physiologic benefits. If we wish to maintain that under certain circumstances it is futile to continue to treat a BMT patient, then a broader interpretation of futility is necessary. There are two distinct dilemmas to be taken into account. First, if it is very likely that the eventual outcome will be nonsurvival, how much life is worth fighting for? Is it worthwhile to continue treatment if the patient may die a fortnight later, still unconscious and ventilated? Is it valid to increase treatment

Table 1. Factors Predicting Nonsurvival in Adult BMT Patients Requiring Intensive Therapy Ref. No.

No. of BMT Patients

Predictors of Nonsurvival

Lung injury, vasopressor requirement, hepatic ⫹ renal impairment (and, less usefully, older age, higher APACHE score, later intubation after BMT) Age ⬎ 40 years, intubation ⬍ 90 days after BMT

2

865 undergoing MV

1

191 undergoing MV

3 4

50 in ITU with respiratory problems 43 admitted to ITU

5

35 admitted to ITU

6 7

25 admitted to ITU Failure of ⬎ 3 organs, septic shock, requirement for MV 10 undergoing MV for GVHD, later intubation after BMT pulmonary complications

Factors Not Related to Survival

Sex, diagnosis or relapse status, graft compatibility, conditioning regimen, duration of MV

94

Type of graft, total body irradiation, reason for intubation

97

Interstitial pneumonia, MV ⬎ 4 days Requirement for MV, higher APACHE score, longer ITU stay Infectious causes of respiratory failure, multiorgan failure

Mortality of Group (%)

82 Type of graft

67

Age, sex, type of graft, conditioning regimen, CMV status, GVHD, use of blood products, TPN, vasopressors, length of ITU stay, APACHE score

77

70

Abbreviations: MV, mechanical ventilation; ITU, intensive therapy unit; APACHE, Acute Physiology and Chronic Health Evaluation; CMV, cytomegalovirus; GVHD, graft-versus-host disease; TPN, total parenteral nutrition.

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to the extent of allowing temporary recovery if the patient is still likely to die within a week or a month? The second problem is how likely is ‘‘very likely’’ (‘‘very likely that the patient will not survive’’). Schneiderman et al,11,p.951 for example, proposed that ‘‘when physicians conclude . . . that in the last 100 cases, a medical treatment has been useless, they should regard that treatment as futile.’’ But why a hundred cases? Why not ten—or a thousand? The concept of futility, fundamentally a medical concept, has been criticized. It purports to be a factual judgment, yet as Callaghan9 pointed out, ‘‘scientific data . . . is ordinarily probabilistic, and even probabilistic data cannot be kept free of value influences.’’ Wolf12,p.199 suspected that the concept of futility may become ‘‘a powerful tool for relieving physicians of the requirement to talk with their patients,’’ and Cranford and Gostin8 suggested that the term might be used ‘‘when the patient is utilising scarce health care resources that should be available for ‘more needy’ patients.’’

the time the decision to withdraw treatment is considered. Bone marrow transplant patients do differ from many other patients in that the potential need for intensive therapy can be anticipated before transplantation; yet, prior ascertainment of a patient’s attitudes toward life support, futility, and modes of dying may not occur. There may be concern about information overload, although physicians generally underestimate patient comprehension in pretransplantation discussions.13 Doctors may not wish to increase patients’ distress by dwelling on delicate issues; of the respondents to our survey, those disinclined toward patient-led decisions were chiefly concerned about provoking anxiety during the necessary discussions. Nonetheless, it has been argued in the U.S. courts that distress is an appropriate reaction to discussion of risks and is required for the patient to make truly informed decisions.14 Further, patients often develop an ‘‘optimistic bias’’ in their assessment of risks or adjust to difficult discussions by adopting denial strategies.15,16 And finally, time limitations and overstretched resources may mean that pretransplantation discussions are less than optimal.

DECISION MAKING

ADVANCE DIRECTIVES

There will never be a scientifically determined threshold of futility, and objective data can only be a framework for the decision to withdraw treatment in BMT patients. Who, then, makes that decision? Among physicians and nursing staff in our own intensive care and hematology departments, opinion was divided about who should take prime responsibility for this decision making. Perhaps surprisingly, only a third of respondents to our survey thought that the patient’s wishes were always paramount and should be determined at the time of deterioration or take the form of a written directive during pretransplant counseling. A third thought that medical and nursing staff should make the decision, provided this was not against the wishes of the patient or the patient’s relatives. The remaining third thought that the involvement of parties in decision making should be determined on a case-by-case basis by the physician concerned. These differing views are not easily reconcilable and reflect the long-standing controversy of medical paternalism versus patient autonomy.

Supposing, however, that the appropriate discussions take place. The next problem lies in interpreting the patient’s wishes. One possibility is the advance directive, advocated by legal and professional bodies in the United States and the United Kingdom.17-20 Advance directives can have a number of problems: they may fail to describe an eventuality or may be ambiguous—their validity rests on the assumption that the patient has correctly envisioned a future circumstance.21-23 They may also have a lack of flexibility for patients to change their minds later. Moreover, although recognition has been given in the last decade to advance requests for the withholding of procedures that prolong life,21,24 the reverse is not necessarily true. Advance requests to have treatment continued against the judgment of physicians are unlikely to be granted the same societal and legal status, although this situation is currently largely untested. Notwithstanding these problems, advance directives have particular application for BMT patients, for because these patients have the dubious advantage of advance warning about a possible fatal outcome, they can at least think about and clearly express their views.

PATIENT AUTONOMY

Whose Life Is It Anyway?

THE ROLE OF THE PROXY

Title of play, Brian Clark, 1977 Perhaps the more contemporary, libertarian view is that each individual should be allowed to make the most important decision of all. Granting patient autonomy to BMT patients, however, may present difficulties. One obvious problem is that the patient is often not competent at

Frequently, the deteriorating BMT patient is unconscious and on a ventilator or is perhaps in a confused state because of medications or infection. If no advance wishes have been specified, the other means of attempting to uphold patient autonomy in this situation is by proxy. Nomination of a proxy may be achieved through an advance directive or it

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may mean involving close relatives in decision making. If the proxy can provide so-called substituted judgment, he or she must have been aware of the patient’s wishes and beliefs.24,25 Yet if this sort of discussion occurs before transplantation, there is no reason such beliefs cannot be transmitted to the physician at that time, so that everyone is clear about the patient’s views and the onus of responsibility is not left with the relatives. In cases in which such discussion did not occur, proxy decision making means acting in the patient’s best interests—really the interests of an average patient in that situation.24,25 But relatives or friends may make their own value judgments; they may be motivated to act counter to the wishes of the patient or they may be reluctant to make such judgments because of burdens of guilt.26,27 Such means of making decisions— through the best guesses of distressed relatives—has nothing really to do with patient autonomy. This is not to say that relatives’ values should be ignored. As Miles28,p.298 pointed out, ‘‘Families have cultural and individual histories of mutually understood family meaning, responsibilities and rituals.’’ For the dying BMT patient, relatives can do a great deal to maintain these cultural and familial ties. For example, Miles argued that requests by the family for continuing of nourishment of the patient be treated with respect and, where possible, honored. Perhaps too little is made in modern society of the religious and cultural rites of passage that surround death; in the often impersonal atmosphere of an intensive therapy unit or hospital ward, the relatives can and should be allowed to make the death of a BMT patient both dignified and personal. THE ROLE OF THE PHYSICIAN

Patient autonomy presents practical difficulties in conveying the right information and in interpreting the patient’s wishes. It also casts the physician in the role of technician and ignores the fact that physicians have their own values that cannot be separated from the facts—for, as we have seen, there is no such thing as a value-free fact. ‘‘The conception of the problem, the choice of language to describe it and the choice of ways to report it are all inevitably shaped by the scientist’s system of beliefs and values.’’29,p.19 A degree of medical paternalism cannot be escaped. However, the structure of today’s society means that a huge burden of responsibility is carried by physicians caring for BMT patients. First and foremost, physicians must attempt to ensure the best outcome and least suffering for their patients. They must also comfort relatives and minimize distress among staff and other caregivers. They have a responsibility to themselves, to their professional reputa-

tions, and to other patients within their units, their departments, and their hospitals and to society to allocate resources for the most appropriate use—not only budgetary resources but also limited resources such as blood products. It is perhaps inevitable that these responsibilities will become confused and will conflict. WITHHOLDING TREATMENTS

If neither total patient autonomy nor total medical paternalism can hold sway, shared decision making may attempt to combine ‘‘technical considerations, patient values and clinical judgement.’’30,p.83 In reality, however, shared decisions are difficult to make, particularly if no priority is given to conflicting views. A more pragmatic approach can perhaps be taken. Consider, for example, a scenario in which a patient expresses a wish not to have his life prolonged in a hopeless situation. Current ethical and legal opinion will uphold this view, whether voiced at the moment of decision or as an advance directive, regardless of opposing views. There are two caveats, relating to issues discussed. It is imperative that as much data as possible are collated, in an attempt to verify the very low chance of survival. Second, it is important that this is or was an informed decision made by the patient with this scenario in mind. This means that time must have been allocated in pretransplantation discussion for the physician to become clear about the patient’s wishes. If these conditions are met, it is almost impossible for the patient’s views not to be considered paramount. It is difficult to give such absolute prerogative to the patient who wishes that everything possible be tried. First, given the futility arguments discussed earlier, there is no obligation for the physician to administer a treatment that will not attain its physiologic objective—ie, one that will have absolutely no impact on the patient’s status. But as discussed, this may be not be a common occurrence. Then there is the issue of causing unnecessary harm to the patient, although it may be unclear how far a patient would really wish to suffer for the sake of ‘‘trying everything.’’ And the question that must arise is how much harm is really being caused to the patient and how much is ‘‘reflected’’ distress of the relatives or the physicians themselves. Stopping treatment to avoid further suffering may have merit but may not be in the patient’s own interests. There is clearly a third reason why a patient’s wishes cannot necessarily be upheld: resources are not limitless. It may be unreasonable, despite patients’ or relatives’ requests, to consider certain treatment measures—expensive therapies, organ transplantations, volunteer blood or tissue donations—when the overall chance of survival is very low. As a consequence, certain boundaries must be set. Nor can such

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boundaries be set by the physician at the patient’s bedside; the physician cannot be an advocate for the patient and for society at the same time. If society wishes to place the responsibility for boundary setting on the physician, then decisions about resource availability must be made in advance. How can this be achieved? One way is for indications to be drawn up for possible interventions so that in any given situation, the physician has a limited range of therapies at his or her disposal. In this situation, everything ‘‘possible’’ may still be tried, but possibilities are no longer endless. To avoid inconsistencies, it would be preferable to attempt professional consensus, in which provision could also be given for the use of experimental therapies, providing that they were registered as such and the results made generally available. A third scenario is possible, in which the patient’s views are unknown. It is very difficult in this case to give priority to potentially opposing views of physicians, relatives, those responsible for resource allocation, and others. In this situation, shared decision making may produce the best, if possibly unsatisfactory, compromise. If strong conflicts arise, local ethical bodies may be able to advise; recourse to external, usually legal, arbitration is rarely practical, given the short time for decision making. This situation can theoretically be avoided through sensitive pretransplantation discussions. WITHHOLDING OR WITHDRAWING LIFE SUPPORT

It may be appropriate or necessary, then, to withhold certain treatments from a deteriorating BMT patient if the overall outlook is believed to be extremely poor. But should therapies be withdrawn under the same conditions? There are arguments that withdrawing treatment is less ethically defensible than withholding treatment, and it has been shown that physicians do distinguish between the two.31 However, it has also been pointed out that making this distinction may lead both to overtreatment, in which instituted treatments are not discontinued, and to undertreatment, in which treatments are not started, because it is believed that once started, treatments cannot be stopped.32 Again, awareness of the views of the patient may help clarify the situation. If the patient has requested not to have his or her life prolonged in a hopeless situation, it would be counter to the patient’s wishes to persist with treatment regardless, and both active treatment and support therapies may be justifiably withdrawn. If the patient has requested that treatment continue until the point of death, it would still be possible to withdraw measures if they were physiologically futile (when they would cease to be meaningful ‘‘treatments’’ or ‘‘support therapies’’). The difficulty arises when treatments are being used to prolong the life of a

patient who is likely to die regardless, when he or she wishes that everything be done but when resources may be more effectively used elsewhere. Sulmasy and Sugarman33,p.221 argued that ‘‘withholding and withdrawing life-sustaining therapy are not morally equivalent acts . . . robbing Peter to pay Paul is different from paying Paul instead of Peter.’’ A more acceptable situation may be one in which limited resources are used according to preset guidelines, albeit guidelines fixed by a balance of overall need and availability. Treatment might then be withdrawn under these guidelines. For example, it may be possible to remove a treatment that had been instigated when there was a possibility of recovery, once the patient has reached a point of likely nonsurvival, irrespective of whether another patient was in need of that treatment. CONCLUSION

Undeniably, withdrawal of treatment from BMT patients already takes place in hopeless situations. It might be argued that ethical debate and attempts to formalize policies are counterproductive, detracting from the wisdom of experienced professional judgment and the treatment of patients as individuals. However, we believe that these issues must be addressed. Without such consideration, there are no measures to judge whether those involved in the care of BMT patients are really taking the best approach, and in our own experience, there does seem to be dissatisfaction with current practice. When asked whether guidelines for terminating life support in BMT patients should be introduced at our own center, the medical and nursing staff on our hematology and intensive care units unanimously agreed that they should. Satisfaction with current practice was particularly lacking among those who have less influence on decisions, namely the nursing staff and junior medical staff. There are four ways in which it may be possible to improve current practice. The first is to increase the data available to determine the chances of survival in particular situations. This would include the reporting of poor outcomes, despite the obvious disincentives to do so. The second is to ensure that the views of individual patients are truly established in pretransplantation discussions, with the use of written advance directives being encouraged. If this is not currently being achieved, consideration should be given to increasing the amount of time that physicians are available for counseling (or increasing the number of physicians available) or to appointing a counselor who can contribute to patient discussions. The third way is to resolve the conflicting responsibilities of the physician. In particular, duties to the patient and to society must be separated, if only by drawing up advance guidelines for the use of particular

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therapies. Fourth, withdrawal of existing care in an accepted hopeless situation should be formalized. Although some centers already have procedures for terminating care in such situations, patient assessments and details and implementation of such procedures vary widely. Guidelines, both for the appropriate use of resource-limited therapies and for withdrawing treatments, would be drawn up with the help of ethical committees, which are otherwise difficult to involve in day-to-day decision making regarding individual BMT patients. While bone marrow transplantation continues to carry a high mortality, those involved have a responsibility to the nonsurvivors as well as to the survivors. Fortunately, objective means of predicting who is likely to die and who

may not are becoming available. It is our responsibility not only to add to this data but to decide how they are best applied. Futility is a medicalized, somewhat artificial concept that does not absolve us from the need for frank and difficult discussions about stopping treatment, and the time for the frankest discussions is before the patient undergoes the transplantation. The wishes of the patient, policies for appropriate use of resources, and a formal procedure for withdrawing treatment are all better clarified in advance, rather than at the bedside of a patient who can no longer have any say. Caregivers’ time at the bedside is better devoted to ensuring a peaceful and dignified death for the patient, a death that is always sad but that is not a ‘‘failure’’ if managed well.

REFERENCES 1. Langendoen K, Caplan AL, McGlave PB: Survival of adult bone marrow transplant patients receiving mechanical ventilation: A case for restricted use. Bone Marrow Transplant 12:501-507, 1993 2. Rubenfeld GD, Crawford SW: Withdrawing life support from mechanically ventilated recipients of bone marrow transplants: A case for evidence-based guidelines. Ann Intern Med 125:625-633, 1996 3. Denardo SJ, Oye RK, Bellamy PE: Efficacy of intensive care for bone marrow transplant patients with respiratory failure. Crit Care Med 17:4-6, 1989 4. Paz HL, Crilley P, Weinar M, et al: Outcome of patients requiring medical ICU admission following bone marrow transplantation. Chest 104:527-531, 1993 5. Afessa B, Tefferi A, Hoagland HC, et al: Outcome of recipients of bone marrow transplants who require intensive care support. Mayo Clin Proc 67:117-122, 1992 6. Torrecilla C, Cortes JL, Chamorro C, et al: Prognostic assessment of the acute complications of bone marrow transplantation requiring intensive therapy. Intensive Care Med 14:393-398, 1988 7. Hollmig KA, Soehngen D, Leschke M, et al: Long-term survival of allogeneic bone-marrow transplantation after mechanical ventilation. Eur J Med Res 2:62-66, 1997 8. Cranford R, Gostin L: Futility: A concept in search of a definition. Law Med Health Care 20:307-309, 1992 9. Callaghan D: Medical futility, medical necessity: The problemwithout-a-name. Hastings Cent Report July-August:30-35, 1991 10. Stanley JM: The Appleton International Conference: Developing guidelines for decisions to forgo life-prolonging medical treatment. J Med Ethics 18(suppl):1-23, 1992 11. Schneiderman LJ, Jecker NS, Jonsen AR: Medical futility: Its meaning and ethical implications. Ann Intern Med 112:949-954, 1990 12. Wolf SM: Conflict between doctor and patient. Law Med Health Care 16:197-203, 1988 13. Lesko LM, Dermatis H, Penman D, et al: Patients’, parents’, and oncologists’ perceptions of informed consent for bone marrow transplantation. Med Pediatr Oncol 17:181-187, 1989 14. Thornburgh v American College of Obstetricians 106 US 2199-2200 (1986) 15. Andrykowski MA, Brady MJ, Greiner CB, et al: ‘Returning to normal’ following bone marrow transplantation: Outcomes, expectations and informed consent. Bone Marrow Transplant 15:573-581, 1995

16. Savulescu J: Rational non-interventional paternalism: Why doctors ought to make judgements of what is best for patients. J Med Ethics 21:327-331, 1995 17. Gilligan T, Raffin TA: Whose death is it anyway? Ann Intern Med 125:137-141, 1996 18. Sommerville A: Remembrance of things past: Oral advance statements about medical treatment. BMJ 310:1663-1665, 1995 19. Fisher F, Macdonald N: Rights and Responsibilities of Doctors (ed 2). London, British Medical Journal Publishing Group, 1992 20. Mclean S: End-of-life decisions and the law. J Med Ethics 22:261-262, 1996 21. Annas GJ: The health care proxy and the living will. N Engl J Med 324:1210-1213, 1991 22. Lynn J: Procedures for making medical decisions for incompetent adults. JAMA 267:2082-2084, 1992 23. Brett AS: Limitations of listing specific medical interventions in advance directives. JAMA 266:825-828, 1991 24. Danis M, Southerland LI, Garrett JM, et al: A prospective study of advance directives for life-sustaining care. N Engl J Med 324:882888, 1991 25. Schneiderman LJ, Arras JD: Counseling patients to counsel physicians on future care in the event of patient incompetence. Ann Intern Med 102:693-698, 1985 26. Seckler AB, Meier DE, Mulvihill M, et al: Substituted judgement: How accurate are proxy predictions? Ann Intern Med 115:92-98, 1991 27. Emanuel EJ, Emanuel LL: Proxy decision-making for incompetent patients: An ethical and empirical analysis. JAMA 267:2067-2071, 1992 28. Miles SH: Futile feeding at the end of life: Family virtues and treatment decisions. Theor Med 8:293-302, 1987 29. Veatch RM, Spicer CM: Medically futile care: The role of the physician in setting limits. Am J Law Med 28:15-36, 1992 30. Lantos JD, Singer PA, Walker RM, et al: The illusion of futility in clinical practice. Am J Med 87:81-84, 1989 31. Caralis PV, Hammond JS: Attitudes of medical students, housestaff, and faculty physicians toward euthanasia and termination of life-sustaining treatment. Crit Care Med 20:683-690, 1992 32. Beauchamp TL, Childress JF: Principles of Biomedical Ethics (ed 4). New York, Oxford University Press, 1994 33. Sulmasy DP, Sugarman J: Are withholding and withdrawing therapy always morally equivalent? J Med Ethics 20:218-222, 1994

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