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Transplants for non-lethal conditions: a case against hand transplantation in minors
  1. Charles E Hedges1,
  2. Philip M Rosoff1,2,3
  1. 1 Duke Initiative for Science and Society, Duke University, Durham, North Carolina, USA
  2. 2 Trent Center for Bioethics, Humanities and History of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
  3. 3 Departments of Pediatrics and Medicine, Duke University Medical Center, Durham, North Carolina, USA
  1. Correspondence to Dr Philip M Rosoff, 108 Seeley G. Mudd Building, 10 Bryan-Searle Drive, Duke University Medical Center, Durham, NC 27710, USA; philip.rosoff{at}duke.edu

Abstract

Human allografts for life-threatening organ failure have been demonstrated to be lifesaving and are now considered to be standard of care for many conditions. Transplantation of non-vital anatomic body parts has also been accomplished. Hand transplantation after limb loss in adults has been shown to offer some promising benefits in both functional and psychological measures in preliminary studies. It has been suggested to expand eligibility criteria to include minors, with one such operation having already been performed. With this in mind, we examine the current state of hand transplantation research in the context of available alternatives. We examine the ethics of carrying out these operations in minors, including under the protections of clinical research. We argue that children should not be considered for this surgery due to the substantial risks of immunosuppressive medication, the likelihood that the graft will need to be replaced during the patient’s lifetime and the lack of significant compensatory advantages over modern prosthetics.

  • transplantation
  • children

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Introduction

Human allograft transplantation of vital organs has proven increasingly successful in saving lives of patients with heart, liver, lung and kidney failure in both adults and children. While by no means benign surgical procedures, they have entered the mainstream of medicine and the demand for organs continues to exceed the supply. Recipients must take lifelong immunosuppressive drugs to prevent graft rejection, thus exposing them to the hazards associated with these drugs, including enhanced susceptibility to opportunistic infections and the development of certain kinds of cancer, but the risks are believed to be worth the benefits (ie, prolonged life with acceptable quality from otherwise fatal conditions). The success with solid organ transplantation has led many to explore using this approach for non-lifesaving allografts, such as transplants of the uterus, face and, recently, limbs, especially forelimbs and hands. Progress with the last has led to the suggestion that the operation be studied in children.1

The sudden loss of a hand, especially one’s dominant hand, can lead to serious functional impairment as well as psychological stress.2 With the introduction of novel experimental prosthetics that provide some sensation to the wearer in addition to improved functional capabilities,3 it is not unrealistic to predict that further technical advances will be forthcoming that will lead to even closer corporal integration and more accurate mimicking of native limb facility (it should be noted however, that these advanced devices are not readily available to patients outside of the laboratory setting). Hence, we must carefully examine the benefits that hand transplantation can provide in the context of alternatives.3 Moreover, it is important to recognise that the patient–subject selection process for hand transplantation clinical research has been extremely rigorous,4 with only a small number of patients deemed most likely to have favourable outcomes being offered the operation. Hence, as with many forms of early phase clinical research, the applicability of both risks and benefits to a larger, more heterogeneous population may be overstated.5 6

Technically similar to hand replantation after traumatic amputation,7 hand transplantation involves a complex microvascular operation followed by the postoperative management of graft rejection, but offers potential restoration of function and body image following limb loss. To date, there have been >85 reported upper limb transplants,8 with one having been performed in a child.4 Hand transplant survival (defined as having a viable graft at the point of survey) is reported in roughly 75% of cases worldwide.9 In conjunction with the current state of immunosuppressive therapies, some physicians believe limb transplantation could be a viable treatment option after amputation.10

Unlike vital organ transplantation, however, hand transplantation is not lifesaving and thus the risks of both the operation itself and those attendant to the postoperative course and continuous immunosuppression must be evaluated in light of this fact. It remains an open question whether the potential benefits of hand transplantation could present an acceptable risk/benefit ratio such that it should be extended to paediatric patients. Indeed, this kind of outcome analysis is applied to many sorts of high-risk, life-threatening treatments when considering whether to either initiate clinical trials or, if they prove promising, to move them into the realm of standard clinical practice.11–13 We will first examine the current understanding and assessment of the benefits and the risks. We will then consider the question of whether children should be eligible candidates. We will present the existing data for this relatively new procedure and discuss the ethics of its proposed use in minors.

Possible benefits of hand transplantation

It is first worth noting that, except for one child, all the available data have been generated from adult patients, and thus the ability to make inferences about their applicability to paediatric patients may be limited. The potential advantages of hand transplantation can be grouped into two categories: functional and psychological. The primary functional benefits include a gain in motor function and sensation, and it has been suggested that hand transplantation could possibly eliminate phantom limb pain, a common and often-disabling complication postamputation for many patients.2

Gaining functional ability after surgery is not an immediate process, as there is a lengthy training period required (due to the length of time for nerve regeneration and innervation of the graft) during which the patient must undergo regular physical therapy, but a consistent increase in motor function has been observed.9 Assuming graft survival, development of some motor function has been observed in almost all patients.14 The degree of capability achieved is variable and dependent on, among other factors, the patient’s strict adherence to the assigned physical therapy routine.3 After an initial learning period, improvements have been variable,5 6 with the majority of patients reporting a steady enhancement in function as they adapt to life with their new hand.9

To date there has been only one study directly comparing the outcomes of hand transplantation and prosthetic fitting, and it suggests that there is very little functional advantage to be gained by the procedure.15 There was no statistically significant difference between the groups in the common tests of hand motor abilities.15 The study did, however, find some psychological benefits of hand transplantation (see below).15 Of note is that this was a single study with a relatively small sample size; that being said, it does suggest that transplantation offers comparatively little gain over the use of modern prostheses. It should also be noted that prosthetic fitting is substantially less invasive and the acquisition of gains in motor ability occurs much more rapidly—a time frame of days-to-weeks rather than years for hand transplantation.16

There is evidence to suggest that transplantation can result in a potential increase in quality of life when compared directly to prosthetics.15 Many of the reported subjective emotional benefits have focused on a sense of feeling physically whole again.3 However, this positive reaction is not universal. For example, the first modern hand transplant lasted only 3 years before the graft was removed at the patient’s request (although this patient had significant challenges with medication adherence, leading to multiple episodes of rejection).17 Very little research has been done on both the psychological outcomes of patients who had  hand transplant and the psychological factors that have the greatest impact on body image integration. However, an adequately selected transplant candidate who is suffering from a significant decrease in quality of life and having troubles with her current body image due to the loss of one or both of her hands may receive psychological benefits from hand transplantation that go beyond that of prosthetics.15

In sum, the field is relatively young and still in an experimental stage, but the utility of upper limb—specifically hand—transplantation appears to be primarily psychological, although there are many patients who do acquire some modest to even significant motor function, although less than exists in native hands. Whether this complex procedure offers sufficient benefit over available alternatives, such as mechanical prosthetics that have been rapidly progressing in complexity and capabilities, remains an open question, but one that could be amenable to study.18 Nevertheless, even modern computer-assisted prosthetics are not without problems of their own, especially for those patients with above-the elbow limb loss, bilateral amputees and the like. It is not unreasonable to suggest that careful patient selection—both psychological and anatomic—could optimise the beneficial effects of vascularised limb allograft surgery. That being said, there are also significant risks associated with allogenic transplantation.

Risks of hand transplantation

As mentioned above, the risk of failed integration of the foreign hand into the patient’s body image can have serious negative side effects including decreased quality of life.17 19 20 Additionally, this procedure carries risks associated with allograft rejection and immunosuppression therapy as well as general surgical risks. While these hazards may be comparable to those experienced by patients receiving livers, lungs, kidneys or hearts, it is generally believed that the latter are offset by the life-saving benefits of these kinds of transplants. The question is whether the potential functional gains and psychological improvements that could possibly be offered by hand transplantation are sufficient to balance the calculable risks.

Minor episodes of rejection are commonly reported in hand transplantation.5 20 These are generally rapidly identified due in part to the high degree of immunological activity skin possesses making the first signs of rejection readily visible.20 While it was initially believed that chronic rejection would not be a significant issue, experience with more patients has demonstrated that, similar to other allografts, low-grade chronic rejection can occur.21 However, there is also no reason to believe that hand transplantation would be substantially different from solid organ transplantation when it comes to chronic rejection and long-term graft survival.5 It may also be true, as it is with organ allografts, that graft survival in retransplantation may be shorter with each subsequent procedure.22 Furthermore, patients who may need (and desire) a second transplantation may plausibly undergo significant psychological distress while awaiting a new limb, especially if they presumably adjusted well to their initial graft. In any case, this would suggest that initial hand transplantation is unlikely to be a permanent solution and patients could require multiple transplants throughout their lives in order to maintain a functioning hand (especially if the first transplant is performed at a young patient age). If this is true, then patients may have to assume the risks of surgery and acute rejection, as well as re-embarking on the process of physical therapy multiple times throughout their lives. But unlike other solid organ transplants, severe rejection episodes in hand transplantation can be dealt with by removing the hand without affecting mortality.23

The most significant risks of hand transplantation are those secondary to the necessity for immunosuppression for the duration of the graft. These primarily include opportunistic infections and malignancies. Other immunosuppressive therapy-related complications that have been reported in hand transplant recipients thus far include hyperlipidaemia, diabetes mellitus, osteoporosis, hip avascular necrosis (requiring hip prosthesis) and renal failure.5 9 14 The risks of rejection, infection, cardiovascular disease, malignancies and so on may be difficult to justify for an operation whose benefits are largely cosmetic with some degree of functional gain.

Nevertheless, with proper patient screening and selective donor matching as well as an assumption that both this operation and the state of immunosuppressive drugs will improve with time, it is not unreasonable that hand transplantation could plausibly move from an experimental procedure into the realm of extremely rare and selective clinical care for well-informed consenting adults.

Hand transplantation in children

While the risks and benefits of solid organ transplantation in children are known and well understood, the presumptive benefits of hand transplantation are much more speculative. Unlike transplanting a heart into a child with irreversible and progressive cardiomyopathy for whom the procedure is life-saving and hence (under the right circumstances and with adequate informed proxy consent) justifies the risks, the same reasoning cannot necessarily be applied to hand transplantation. If we assume that the potential advantages of limb transplantation in children would at least superficially be similar to those in adults, and if done sufficiently early in life (say, before the age of 5 years) could be greater (in terms of incorporating the allograft into the patient’s sense of bodily self), then any possible risks or harms must be assessed with these in mind. Due to the unique vulnerable status of paediatric patients, there are a number of additional ethical concerns that must be considered when discussing whether they should be eligible for an experimental treatment. For example, the long time course of the potential consequences (side effects) of the operation (namely, the requirement of graft lifelong immunosuppression) gives rise to concerns regarding consent. Since a child is unable to give meaningful informed consent, surrogates would be submitting the child, and the future capacitated, autonomous person they will become, to a life of extra medical burdens and risks. Of course, this is true for many clinical interventions in children—the most obvious parallel being solid organ transplants. However, a major difference between most solid organ transplants and a hypothetical one for hand transplantation would be that the former involves treatment for a life-threatening condition. Moreover, many of the success stories surrounding hand transplantation involve the operation being performed years after the initial amputation,3 20 and there is currently no evidence to suggest that outcomes can be improved by performing the operation sooner after limb loss. Indeed, a history of inability to incorporate prosthetics into one’s body image seems to improve the likelihood of the patient integrating their new hand into their body image and therefore having better overall outcomes.3 These observations suggest that the complexities associated with paediatric participation could be avoided by simply waiting until these patients reached the age of majority and hence could give first person consent themselves.

Nevertheless, a postulated psychological benefit specific to paediatric patients could be more pronounced by allowing for ‘normal’ social development that may be otherwise hampered by disability. For instance, many young patients with chronic disease have a harder time achieving various developmental milestones.1 Proponents of hand transplantation in children suggest that this procedure could allow for a more normal development absent the ‘aesthetic and social cost’ associated with prosthetics.1 However, long-term immunosuppressant therapy has been framed as a chronic disease on its own,15 thus potentially trading one chronic condition for another when it comes to childhood development. Further, immunosuppressant therapies have been shown to lead to stunted growth and the development of facial hair in women.23 Combined with the fact that we cannot know if the transplanted hand would grow as the child does,1 the social benefits to be gained by the child having a hand rather than a prosthetic may not be as clear, and may be viewed with some degree of misgiving.

Non-adherence with immunosuppressive therapy in paediatric solid organ transplant recipients, particularly in adolescents, reported as being 30%–75% of patients,1 24 make rejection a serious concern. Indeed, a major cause of diminished graft survival longevity in this patient population is due to poor compliance.24 Further, high non-compliance rates on their own present serious potential problems due to the sensitive nature of the recovery process for this operation. It has been observed that even ‘trivial’ complications, such as influenza, can have large impacts on the outcomes of patients who had hand transplant.6

If chronic low-grade rejection and long-term limb viability are issues, as they are with other allografts, then the transplanted hand should be expected to be removed at some point in the future. Although there has been no report of average expected graft survival, if we perhaps assume that it is comparable to that of kidney transplantation, then the transplanted hand can be expected to survive for about 15 years (within the 8–20 year reported range for kidney transplantation).25 Thus, a child who was transplanted at age of 10 years might be expected to undergo this operation again with all of the subsequent risks and time dedicated to physical therapy in her mid-20s. Further, if these transplants are similar to solid organs, graft survival would be expected to diminish successively.22 Provided limb viability is an issue, this procedure would therefore be prescribing a number of operations and potential medical complications to the child throughout her life.

Arguably, the largest concern with immunosuppressive therapies in this context is the increased chance of malignancy.26 Younger patients have a higher chance of developing a malignancy than older transplant recipients.1 A recent study by Yanik et al has shown a higher incidence of a number of cancers in paediatric patients who received solid organ transplants (with non-Hodgkin’s lymphoma alone occurring 212 times more frequently than would be expected in the patient population).27 These tumours can themselves be life threatening. And while some may be amenable to treatment with decreasing dosages of antirejection medications, many others require intensive, multiagent chemotherapy,28 an additional risk that seems difficult to justify to maintain a graft that may be both temporary and non-lifesaving.

There may be a unique exception to our argument against employing this procedure in minors. In 2015, the first paediatric hand transplant was performed.29 This transplant was performed on an 8-year-old boy who lost both hands due to sepsis and associated ischaemia.1 The patient had already undergone a kidney transplant and was unable to integrate upper limb prosthetics into his life in a useful way. Since the patient was already on immunosuppressive therapies, the additional risks we have described would be substantially minimised. Similarly, the potential functional benefits for this patient could be greater as he lacked both hands. As of 18 months postsurgery, the patient has experienced numerous rejection episodes that were successfully treated and is currently maintained on a more rigorous immunosuppression therapy protocol than before the transplantation (requiring four immunosuppressive drugs rather than the two it took to maintain his kidney).29 This is notable as there is some evidence of a dose-dependent relationship between long-term steroid use for immunosuppression and postoperative death due to cardiovascular disease or infection.30 Subsequent to this increase in immunosuppression, the patient has experienced several minor infections and a rise in serum creatinine. On the other hand, the patient has experienced promising functional outcomes.29 Nevertheless, it is worrisome that the justification for performing the transplant in this patient was that doing so would not expose him to an increase in risk from immunosuppression, but this has apparently not been the case. While this case is interesting as a perhaps one-off treatment in a highly unusual clinical situation, its very existence does not appear to negate the very real and calculable risks associated with hand transplantation in either adults, or especially, children. Taking the potential benefits and the possible as well as actual harms into account for young patients who have traumatic, surgical or congenital forelimb loss, it is difficult to justify proceeding with further exploration of this procedure as a therapeutic possibility. It is also worth noting at least a theoretical additional concern with obtaining donor limbs for child recipients. It has long been observed that the parents of dead paediatric patients donate organs in a relatively higher percentage than adults, often attributed to the wish to memorialise their deceased offspring by giving life to other children.31 32 It is conceivable that parents might be less likely to give permission for donation for a transplant that is not lifesaving. However, it is unlikely that a limb would be removed without the vital organs at the same time (although possible), making this scenario more a speculative concern.

Conclusion

Advances in microsurgery techniques and immunosuppressive pharmacotherapy have permitted transplant surgeons to experiment with allografts of non-vital organs for non-life-threatening clinical indications. The justifications advanced for developing such procedures, specifically hand transplantation, have been based on the potential for restoration of previous body image as well as a potential gain or restoration of premorbid function. Based on reported results, it appears that the benefits attained over modern-day prosthetics are largely cosmetic and psychological in nature, while the risks are serious and exist as long as the graft is in place.

We recognise that our discussion and argument against proceeding with even experimental hand transplantation in minors may be thought by some to be premature given the state of the art in this field. However, with one such operation having already been performed as well as the relatively recent establishment of a paediatric hand transplant programme at a major children’s hospital,33 it is clear that it is being seriously considered to expand eligibility criteria to minors. We believe that this would be a significant error, by exposing a paediatric population to significant risks without compensatory benefits necessary to justify the burdens. This calculus is different in adults. When offered to subjects with full autonomous decision-making capacity and the ability to actively engage in, and give, valid informed consent, these possible risks and benefits can be carefully evaluated by first-person authorisation, where the risks inherent in surrogate decision-making are avoided. Presumably, individuals capable of making rational decisions could choose (or not) to enroll in these studies. However, if hand transplantation were expanded to include minors, for whom consent would be by proxy, a more favourable benefit-to-risk ratio must be demonstrated.

Subjecting a child to a life of intensive physical therapy, risk of acute and chronic rejection, and, most worrisome, substantially higher risks of cancer, infection and cardiovascular disease would require the promise of extensive medical benefits. With our current understanding of hand transplantation, the benefits that can be hoped for are some improvement in function over prosthetics and an improvement in body image. Since the functional benefits are modest at best, it is possible that this operation fulfils more of a cosmetic role and should be evaluated as such. This is not to say that further advances in the field as more experience is gained with adult subjects would not alter the current risk–benefit profile at some point in the future. But at the present time, our analysis of the current state of affairs suggests that children should not undergo hand transplantation at this time. Of course, one could also apply this analysis to limb transplantation for anyone and ask whether its dangers are outweighed by its potential dividends. With adults, it could be argued that their ability to give informed consent compensates for the narrow risk–benefit ratio and hence serves as a justification for proceeding. However, we are not entirely convinced that the simple existence of consent is sufficient to endorse limb transplantation. That being said, it is not unreasonable, ethically or medically, to proceed with the cautious clinical investigation of the procedure under conditions in which autonomous first-person consent can be maximised.

This discussion also raises the important question about whether any non-lifesaving allografts should be ethically acceptable for anyone, irrespective of age, given the risks. While outside the scope and specific aim of this paper, it is not unreasonable to address this issue, as these procedures have become more common. Aside from limb transplantation, the two that have received the most scrutiny (and remain experimental) are face and uterine transplants in adults. The latter, however, are temporary and the organ is removed after delivery of the infant. While the former is aimed towards cosmesis in the circumstances of severe facial injury and disfigurement, it has been plausibly argued that the inherent value of the face to human social interaction and quality of life is such that it may be worth the risks.34 We reserve special consideration for these procedures in minors, primarily because of the issue of consent, as we have described. Permitting surrogates—although well-meaning proxies such as parents—to make these judgments for such a hazardous venture without compensatory benefit, all the while knowing that there is a high likelihood that the graft will not last for the lifetime of the patient, seems excessive.

In some respects, our argument is similar to one that has been advanced to limit the availability—and bar it completely in some situations—of aesthetic cosmetic surgery for minors. Even those who contend that there are clearly clinical cases in which elective surgery for cosmesis alone is defensible, such as breast augmentation and rhinoplasty to alter the patient’s appearance in the absence of a congenital malformation or anatomic dysfunction, agree that careful prescreening of patients is necessary.35 36 It is worth noting that the caution urged before proceeding with these kinds of interventions are generally concerned with issues of consent and the risks and benefits of procedures that while physically altering and involving immediate risks are generally considered to be relatively safe in the long run.37 38 Nevertheless, it is widely accepted that young people have decreased ability to appreciate the benefits, burdens and risks of these surgeries, especially when coupled with the enormous psychological and emotional overlay associated with altered perceptions of self body image.39 40 Indeed, it is likely that most minors seeking aesthetic cosmetic surgery would be denied access due to these concerns. As we have proposed, these misgivings should be proportionally greater when the surgery and its aftermath involve significantly greater risks, such as those associated with limb allografting.

We must emphasise that our analysis and conclusion should not be taken to minimise the potentially disastrous effects that losing a limb can have on an individual’s quality of life, just that hand transplantation may not be the most appropriate therapeutic solution. Further, with the clear lack of available data regarding this operation in general and as it relates to paediatric patients, more research in a range of areas (eg, functional outcomes, lifespan of the transplant, psychological factors related to patient decision making and so on) is essential to be able to make a better-informed decision regarding the appropriateness of this operation in the future. With the less than favourable risk/benefit ratio and the ability to delay the operation until meaningful consent can be acquired, we believe it is clear that hand transplantation is an operation for which children should not be eligible.

References

Footnotes

  • Contributors Both authors contributed equally to the crafting and writing of the paper.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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