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The rationale for hand transplantation.

2002; Wolters Kluwer; Volume: 74; Issue: 6 Linguagem: Inglês

10.1097/00007890-200209270-00001

1534-6080

Vivien C. Lees, Steven J. McCabe,

Organ Donation and Transplantation

Hand transplantation became a clinical reality in 1999 when a hand transplantation was performed in Lyon, France (1). As anticipated, this event has excited the public and professional imagination, and a small number of similar transplants have followed. Before this, there was one unsuccessful attempt at transplanting the hand undertaken in Ecuador in 1964 (2). Recent cases include 14 transplant recipients with 10 unilateral and 2 bilateral hand transplants. There have been no early losses of the transplants from microsurgical failure or acute rejection. There has been no mortality, and from the limited published information available, morbidity has been controlled by standard therapeutic maneuvers (3–6). Nine hands are known to have survived at least 1 year (W. C. Briedenbach, personal communication, 2001). ETHICAL CONSIDERATIONS AND INDICATIONS To date the procedure remains experimental with no consensus that the procedure should be performed at all (7–9). The crux of the ethical dilemma over whether to proceed with hand transplantation lies in consideration of the state of “equipoise” (10). Equipoise is the situation of uncertainty in which the clinical investigator regards the potential outcome of an experiment or clinical trial as truly balanced between its potential for benefiting the patient or for causing unintended harm. The overall potential harm to the patient should be at least balanced and preferably outweighed by the potential benefit (11). The decision to offer a hand transplant to a patient should be based on what can reasonably be inferred of the risks and benefits from studies of function after hand replantation (microsurgical reconnection of the severed body part), rejection phenomenon, and morbidity in clinical cohorts of solid organ transplant recipients. Decision analysis is a method used to make the best decision in the face of uncertainty, and one such analysis has been undertaken in the (then) hypothetical situation of hand transplantation (12). In this theoretical model, the recipient who maintained good health was shown to be more important than retaining the transplant, if problems arise. In situations in which poor health can be controlled by removing the transplant, the balance shifts in favor of performing the transplantation. The precedent already exists for treatment of non-life-threatening conditions by transplantation. Although a hand transplant is not equivalent to a renal or pancreatic transplant, it is also performed for “life quality.” The standards for therapeutic innovation (Moore’s criteria) are pertinent when such treatment is contemplated. There should be adequate scientific background for the treatment and considerable skill and experience in the team (field strength), the institution should foster an ethical climate and an open approach to presenting relevant plans and protocols, and the results should be available for public scrutiny (10,11). In practice this means that the team establishing a hand transplant program should have associated (laboratory) research, hospital ethical committee approval, and a high caliber surgical staff with a proven track record. The team should have met with relevant patient representative groups and should publish their results for peer scrutiny. A full debate should be conducted both with the public and within the profession. The difficulty of providing truly informed consent is a real one. Although there are many genuine uncertainties regarding the outcome of hand transplantation, there is a body of information in the replantation and existing transplantation literature that does provide relevant information. Most patients do not make a numerical calculation about relative risk in the consent process and are swayed by other factors in making their decisions. It is therefore important that the consultation and consent are undertaken in as objective a manner as possible, probably with the assistance of a patient advocate. The complexity of the consent issue would be compounded were the recipient to be a child. POTENTIAL BENEFITS OF HAND TRANSPLANTATION The potential benefit of a hand transplant is to provide a hand that would work at least as well as the equivalent replant. Potential gain in function, restoration of a more normal body image, and eliminating the irritating sense of the “empty space” that is part of the phantom limb phenomenon are the principal reasons cited by upper limb amputees for considering a hand transplantation (13). The benefits of hand transplantation are likely to be greater in the bilateral amputee. Bilateral hand transplantation could potentially make the difference between autonomy and dependency in daily living. Decision-making analysis shows that the utility (a numeric value assigned to health outcome) is greater for the bilateral than the unilateral hand transplant (12). Some argue that hand transplantation should only be considered for the bilateral case (7). This issue remains subject to debate and requires the development of better outcome indicators along with collation of units’ experience for its resolution. The hand transplant operation is essentially similar to a hand replantation using standard hand and microsurgery techniques (14). Since the first upper limb replantation was performed in 1962 (15), successful salvage of amputated limbs has become routine in microsurgery centers, with overall limb survival rates quoted at 67% to 87% (16–18). Excellent results can be routinely achieved. Patients report that a replanted limb is more useful than a functional prosthesis (16). Analysis of one replantation series showed finger movement normal or near-normal, grip strength at least half of normal, and key pinch approaching normal. Protective sensibility is restored in most cases, but two-point discrimination and intrinsic muscle function remain poor (19). The best results are achieved in the clean-cut or “guillotine” injury. Critics of hand transplantation argue that upper limb amputees usually have had crush or avulsion-type injuries that caused the failure of an attempted replantation and subsequently leave a scarred bed that would be unsuitable for transplantation. Even now, not all patients with hand amputations are referred for replantation. Further, although a crush injury may contribute to replant failure, it does not exclude proximal stump revision at the time of transplantation to effectively recreate the guillotine injury. The level of the replant is an important determinant of outcome in limb replantation with section in the distal forearm and wrist obtaining the best function. Important advantages in the transplantation situation include the following: ability to select and educate the patient, shorter warm ischemia of the donor hand, and offset level of section of the various structures to minimize confluent adhesion formation. Best results are likely to be obtained where interpositional nerve grafting is avoided in the nerve repairs and where stimulation and histochemical staining are used to match sensory and motor fascicles (7). CLINICAL AND LABORATORY EXPERIENCE OF COMPOSITE TISSUE ALLOGRAFTING (CTA) Clinical and laboratory studies have defined the parameters of CTA. Control of skin and muscle rejection (20) and good quality nerve regeneration are the keys to successful hand transplantation. Nonvascularized skin allografts are highly antigenic but can be maintained indefinitely using cyclosporine in a rat model (21). Matching of RhLA-A and -B antigens increases skin graft survival time. Vascularized skin rejects less vigorously than nonvascularized skin (20). Recently a system of scoring of skin rejection in a swine CTA model has been developed (22). Animal studies of various vascularized CTA have shown graft survival and normal or near normal function (23–26). Primate studies, while showing limb transplantation is possible with medium-term viability and function including nerve regeneration, suggest that most transplants do badly (27–29). There has been concern over the use of primate models for CTA. The immunosuppressive regimens used in the published hand transplants were closer to the pig rather than the primate models, demonstrating the utility of the former for future research (5,6,26). Clinical experience with vascularized CTA is limited. Vascularized flexor tendon units and vascularized nerve allografts have been transferred using temporary immunosuppression and have functioned in the long term (30,31). Vascularized skeletal muscle for scalp reconstruction and vascularized allograft knee joints and femoral diaphyses have been successfully transplanted under immunosuppression (32–34). The early experience of hand transplantation has been promising (1,5). Function has now been measured in three hands at least 6 months after transplantation using the Carroll test (35), a sensitive indicator of integrated functional recovery. This test assesses dexterity by asking the patient to manipulate small objects in various simulations but does not confirm that the hand transplant is integrated into bimanual activities of daily living. In this system, one of three hands was classified as good, and two of three hands was classified as fair. Protective sensibility with return of temperature, pain, and pressure sensation were achieved along with modest grip and key pinch functions (6). The final results may be better than this interim analysis suggests. Some nerve fiber types regenerated more rapidly than expected possibly because of some action of tacrolimus (6). At this time there is a clear need for further development of outcome indicators that would facilitate assessment of the overall benefits of hand transplantation. POTENTIAL RISKS OF HAND TRANSPLANTATION The risks to which a hand transplant recipient would be exposed have been anticipated from the literature on morbidity of solid organ transplantation. Risks common to all solid organ transplants are principally those of the immunosuppression. The potential recipient of a hand transplant is likely to be healthy, unlike the recipients of many solid organ transplants. Concurrent illness must be a relative contraindication to hand transplantation, although some advocate undertaking hand transplantation only on patients who have already had a solid organ transplant (7). Rejection of the hand transplant or its loss from other causes should not be a life-threatening event by contrast with loss of some solid organ transplants. Appropriate monitoring of the hand transplant should allow detection of potentially life-threatening complications, followed by effective treatment, which might include removal of the hand. Virtually all patients with solid organ transplants experience multiple complications, although not necessarily major ones. The same could reasonably be anticipated for hand transplant recipients. Psychological Morbidity Patients undergoing hand transplantation early in the program will be subjected to intense media scrutiny and need to be prepared for the same. The medical team should avoid decisions based on a desire for favorable publicity and simultaneously should avoid potential recipients who are strongly motivated by the desire for publicity. The sustained input of a clinical psychologist would be needed to support the patient. The procurement of donor limbs raises particular issues that do not arise in solid organ transplantation. Namely, the donor would suffer visible external disfigurement, and this might prove unacceptable both to potential donors and their families. A survey of one population of potential donors showed that 80% who would be prepared to donate solid organs would also be prepared to donate hands, although some stated that their families might have objections (13). Matching of the donor limb to the recipient with respect to gender, skin color, and size is anticipated, but the new limb may still look different from the normal hand. This might lead to psychological difficulties in acceptance and integration of the new limb. Operative Morbidity and Mortality The perioperative mortality of hand transplantation should equate with that of any major limb surgery and is principally that of the anesthetic. Using regional anesthesia, operative mortality should approach zero. Limb loss from vascular complications should be less than 3% to 5% (the failure rate of elective microsurgical transfers performed in specialist centers). Infective Complications Infections are the most common complications seen in solid organ transplantation, tending to occur within months of transplantation (36,37). Bacterial infections are commonly site specific (38). Of the viral infections, the herpes group are a common source of morbidity (38). Potential recipients with hepatitis or human immunodeficiency virus need to be excluded. Cytomegalovirus (CMV) matching of donors and recipients is desirable. CMV mismatch was accepted in the Louisville case but did lead to complications from the infection (4). Given the respective sizes of the potential donor (large) and recipient (small) pools, such matching should be feasible. Fungal infections are potentially lethal and may be difficult to detect (39). Opportunistic infections become relatively more common with time (37). The good health of the hand transplant recipient should reduce the disposition to infection. Rejection It is axiomatic that the level of immunosuppression required to control rejection should not exceed an “acceptable” degree of systemic toxicity. Final function will be influenced by the success in controlling rejection episodes and by the quality of nerve regeneration. Rejection in the hand transplant can be monitored by serial skin biopsy samples, and rejection may be detected histologically before it becomes apparent clinically. Interestingly, recipient Langerhans cells appear in the hand skin after a number of months (3,4). Other cell types may be replaced in the longer term. Flow cytometry analyses have to date shown no evidence of induction of chimerism in hand transplants (6). Chronic rejection in solid organ transplantation seems more likely where acute rejection has occurred previously (39). Of the cases published to date, two of the four cases had experienced acute rejection and both of these had had three such episodes within the first 8 months. All acute rejection episodes responded successfully to standard modifications of immunosuppression (6). Interestingly the two cases that had no rejection had only three HLA mismatches compared with six mismatches in those that did reject. Interpretation of this observation is confounded because the Guangzhou patients were treated with higher doses of steroids than the Lyon and Louisville patients. The role of HLA matching therefore remains uncertain at this time, although in theory might be expected to significantly reduce the incidence of rejection episodes (40,41). It is worth commenting that in an established hand transplant program, there could potentially be many more donors than recipients and HLA matching may therefore be feasible. Graft-versus-host-disease has not been observed in the published hand transplant cases. The Guangzhou team scraped out the bone marrow on one of their hands and in addition irradiated one of the hands (6). Neoplasia The development of non-Hodgkin’s lymphoma is a lethal nonreversible complication largely confined to those who are seronegative for Epstein-Barr virus (EBV) (42). Other lymphoproliferative disorders are typically reversible (43). One study demonstrated a relative risk for squamous cell carcinoma after solid organ transplantation of 50%, with the mean interval from transplantation to formation of squamous cell carcinoma being 3.5 years. This risk is influenced by skin type and the level of sun exposure (44). One multicenter study in a renal transplant population put the risk of nonmelanoma skin cancer at 11.1% during the first 3 years (45). Drug Toxicity The toxicity of immunosuppressive drugs is well documented in the transplantation literature. Reactions may be idiosyncratic, dose related, reversible, or irreversible. The combination regimens used in hand transplantation to date have included tacrolimus (FK506), mycophenolate mofetil, and prednisone. Basiliximab, antithymocyte globulin, and CD25 monoclonal antibody have been used variably (5,6). Reported toxicity to date includes transient hyperglycemia that responded to appropriate therapy and a Cushing’s-type syndrome in one of the Guangzhou cases where relatively high doses of prednisone had been used (6). RISK REDUCTION STRATEGY There must be a small but finite risk of death associated with performing a hand transplantation. There are reasons to believe this figure could be kept to a very low level by appropriate surveillance, with the option to withdraw immunosuppression if a potentially lethal complication developed. A decision to remove a functioning, and otherwise successful, hand transplant might have to be made. It is conceivable, even so, that the health of a patient might be permanently impaired even if the transplant were successfully removed. Surgical removal of the hand transplant should also be considered if immunosuppression produced unacceptable chronic morbidity or if infection, refractory to antibiotic treatment, develops in the transplant. A higher level of risk of rejection could be accepted as a specific risk-reduction strategy to reduce the dosage of immunosuppressive drugs. Infection risks can be further reduced by CMV matching of donor and recipient, screening of donor and recipient for EBV, and possibly exclusion of an EBV-negative recipient. The risk of lymphoproliferative disorders may be reduced by avoiding the use of monoclonal antibodies. Although controversial, there may be a place for HLA matching of donor and recipient. Minimizing the use of steroids would reduce morbidity. The development of skin neoplasms could be reduced by avoiding sun exposure and using sun block creams. Pretreatment of the allograft could include removal of bone marrow from forearm long bone to reduce the chance of graft-versus-host disease (46). Further, the psyche of the patient needs to be taken into consideration, with counseling both before a decision regarding transplantation is made and continuing in the postoperative period. Appropriate case selection is clearly important to success. Potential hand transplant recipients should undergo formal psychological assessment with a series of consultations before making any decision regarding transplantation. The Louisville experience shows that only a few percent of potential recipients are likely to be suitable candidates to receive a transplant for reasons that are multifactorial (W. C. Briedenbach, personal communication). CONCLUDING COMMENTS Until recently there was great skepticism that rejection could be controlled in a hand transplant. The few such transplants performed to date have confounded that expectation, and valuable observations have been made. It would seem that the equipoise condition may now exist in regard to hand transplantation. The treatment objective for a hand transplant is to achieve at least the same function as a hand replant, with the lowest possible morbidity from the immunosuppressive regimen. Clearly improvements in immunotherapy and immune modulation will shift the balance in favor of performing a transplantation. At this time the available evidence would suggest that there is a good case to be made for performing hand transplantation in highly selected patients. It is unlikely that hand transplantation will attract public funding until the benefits of such intervention have been more clearly established. For the time being, cases are likely to be funded privately in association with academic transplantation programs. For all the complexity surrounding this potential treatment, it is the patients who motivate their surgeons to explore this option and it is the patients who will ultimately decide whether a hand transplantation is in their best interests. Acknowledgments. The authors thank J. Wallwork for advice in the preparation of this manuscript.