Ethical considerations in composite tissue allotransplantation

Ethical issues posed by the hand transplant program conducted by hand and plastic surgeons at Jewish and University Hospitals, Louisville, Kentucky, are examined in this essay. Because a composite tissue allotransplantation (CTA) is an experimental procedure, it raises issues as to the protection of human subjects. The background for the emergence of medical ethics as a discipline is indicated and the processes employed by the CTA team in order to address ethical concerns are discussed. Questions are posed as to the justifications for certain procedures and those pertaining to the goals of medicine, informed consent, and patient quality of life. Other issues include benefits versus risks, patient autonomy and medical paternalism or non-maleficence. The Louisville team seems to have dealt conscientiously with all ethical questions that have been posed and has treated the hand recipient with competence and continuity of care. No reasons based in ethical concerns have surfaced that would in any way discredit the program.     

No man's land revisited: the primary flexor tendon repair controversy

New surgical procedures, novel concepts, and/or the presentation of very good results with an apparently discredited technique meet varying degrees of resistance among the establishment of any profession. In hand surgery this phenomenon was exemplified in a striking fashion with the presentation of a controversial report entitled, "Primary repair of flexor tendons in no man's land" by Kleinert, Kutz, Ashbell, and Martinez of Louisville, KY, at the 1967 American Society for Surgery of the Hand (ASSH) annual meeting. The discussant, Joseph Boyes, expressed such skepticism that a special ASSH committee was appointed to go to Louisville and review the results to determine if they were as good as claimed. They were, and today primary flexor tendon repair is the procedure of choice for most flexor tendon lacerations.     

Past, present, and future research in the field of composite tissue allotransplantation

In September 1998, a surgical team in Lyon, France, performed the first successful hand transplant. After this historic event, in January 1999, the University of Louisville performed the first hand transplant in the United States. These events sparked interest and debate concerning the justification of performing limb allotransplantation. The field of composite tissue allotransplantation (CTA) has made significant advances in the past two decades, yet advancement of the applications of CTA into the clinical arena had been fairly limited to this point. The most inherent controversy in CTA involves the fact that the clinical applications for the most part involve restoration of function and/or structural integrity. These procedures are done essentially for quality-of-life concerns, not life-saving issues. Present concern involves subjecting CTA recipients to a lifetime of postoperative immunosuppressive therapy. We cannot fully understand where we stand at present and in what future directions the field is heading unless we have an understanding of where we have been in composite tissue transplantation. This article reviews the historical aspects of CTA, discusses the present state of CTA, and speculates on potential future applications of CTA.     

Ethical considerations in the early composite tissue allograft experience: a review of the Louisville Ethics Program

This paper reviews the formulation and evolution of the ethical component in one of the earliest clinical composite tissue allograft (CTA) programs, the hand transplantation program in Louisville, Kentucky, USA. The purpose was to derive lessons and define principles to give guidance for future programs and introduction of new CTA. We reviewed the initial ethical considerations, including input from respected ethical scholars, guidelines for innovative procedures transparency in public and professional scrutiny, and compliance with human studies regulations (IRB approval). We found the initial focus on ethics, scholarly input, guidelines for innovative procedures, and human studies protection regulations to be valid. Moreover, we noted the effect of autonomy in subjective, quality-of-life benefits on equipoise and effective risk-benefit analysis in effective informed consent. We found that psychiatric screening and support to be exceptionally valuable in protecting autonomy, suitability for participation, assessing personality organization, and determining compliance ability. We conclude that the program ethical principles were validated. For future CTA programs and procedures, we recommend an ethical emphasis with adherence to high standards and transpire to independence to scrutiny and oversight. We recommend protection of autonomy judgments in equipoise judgment and informed consent. We recommend skilled psychiatric screening and support. We endorse scholarship, scientific accuracy, and data sharing.     

The first (double) hand transplantation in Turkey

In September 2010, a bilateral hand allotransplantation was performed on a 28-year-old man who had suffered amputations at the level of 1/3 of the proximal forearm on the right and 1/3 of the distal forearm on the left 2 years previously. This was the first hand transplantation case in Turkey. Preoperative organization, legal difficulties, technical aspects of the operation, and immunosuppressive regimen are detailed herein. The early results of the first composite tissue allograft (CTA) transplantation are also reported. The results were encouraging for all future types of CTA transplantation, including hand and face. Following the early promising outcome of the first case of hand transplantation in Turkey, we have accelerated preparation of regulations for CTA transplantation, including hand and face allotransplantation.     

Patient compliance with a rehabilitation program after flexor tendon repair in zone II of the hand.

The use of early mobilization during rehabilitation of a finger after flexor tendon repair in zone II has achieved worldwide acceptance. Different exercise instructions are given to patients in different clinics, however. When using Kleinert dynamic splinting, some hand therapists instruct patients to exercise 10 times an hour, while others tell their patients to exercise as many times as possible. How often a patient should exercise to achieve optimal results has never, to the authors' knowledge, been investigated. To identify a relationship between exercise behavior and range of motion achieved at 6 months postoperatively, the authors started a pilot study of the compliance of 15 patients with a rehabilitation program following flexor tendon repair in zone II. A portable rehabilitation device was used to deliver an isotonic tensile force and to record when (during the day) a patient exercises and how many exercises the patient performs. Patients were instructed to perform at least ten exercises per hour. The average count per hour was 69 exercises (range, 14-213). In this small group study, no strong correlation was found between exercise count and the total active or total passive motion achieved.     

Immunological tolerance as an adjunct to allogeneic tissue grafting

Since its clinical inception, our group has worked in clinical and experimental transplantation. The exciting early results of composite tissue allografts (CTA) attracted our attention during the 1980s, when some of the first experimental CTA literature appeared. The recent extraordinary results of clinical CTA grafts, primarily the Louisville and Lyon results, have been highlighted at this meeting. Interestingly, this success followed not long after the first International meeting in Louisville in 1997. This is clearly an exciting new application of transplant techniques to one of the newest and most unique types of transplants. Previous studies used immunosuppression for skin allografting. Early results seem quite exciting and we expect to see a rapid growth of interest and activity in this area. We believe that the entire field would benefit from the novel, highly effective and minimally toxic immune tolerance induction using CD3-immunotoxin (CD3-IT) and deoxyspergualin (DSG).     

Investigation of risk acceptance in hand transplantation

PURPOSE: Twenty-four hands have been transplanted in 18 individuals and clinicians continue to debate whether the risks justify the benefits in these procedures. To assess quantitatively the risks versus benefits in hand transplantation we used a validated instrument (Louisville Instrument for Transplantation) to measure the degree of risk individuals are willing to accept to receive different types of transplantation procedures. METHODS: The Louisville Instrument for Transplantation contains 237 standardized questions that incorporate modified standard gamble and time trade-off outcome measures and questions that assess body image perception, depression, self-esteem, optimism, socially desirable responding, and demographics. Respondents were questioned on the extent to which they would trade off specific numbers of life-years or sustain other costs in exchange for receiving 7 different transplantation procedures. For this study we questioned 227 individuals in 4 study populations with differing life experiences: healthy individuals, organ transplant recipients, upper-extremity amputee patients, and lower-extremity amputee patients. RESULTS: All populations questioned perceived risk similarly despite their differing life experiences and would accept differing degrees of risk for the different transplantation procedures. Organ transplant recipients were the most risk-tolerant group whereas upper-extremity amputee patients were the most risk adverse, even when considering a single hand transplant. All groups that were questioned would accept a higher degree of risk to receive a double versus a single hand transplant. CONCLUSIONS: By questioning individuals who have experienced directly the risks of immunosuppression and those who could benefit from hand transplantation, this study presents an empiric basis for assessing risk versus benefit in this procedure.     

Controlled mobilization after flexor tendon repair in zone II: A prospective comparison of three methods

A new controlled-motion program that incorporates dynamic flexion traction to all four digits, a short splint leaving the interphalangeal joints free, and a nighttime extension splint was prospectively compared with a modification of the Kleinert technique and a combination of the modified Kleinert technique and passive movements. Each program was applied to approximately one third of 178 consecutively treated digits with tendon injuries in zone II. The mean total active interphalangeal joint range of motion 6 weeks and 1 year postoperatively was significantly better and extension deficits were significantly less frequent in the digits mobilized with the new program. The postoperative treatment input, in terms of frequency of reviews and time spent in therapy sessions, is not greater than with more traditional controlled-motion programs. Our results indicate that the new program is a safe, reliable, and cost-effective method that produces very good results in a general population.     

Recipient screening and selection: who is the right candidate for hand transplantation

Hand transplantation is an elective non-life saving but quality of life-giving surgery for good candidates that is not without risk. Patient screening and selection is the most critical element to successful transplantation outcomes and cannot be overemphasized in terms of importance in the overall scheme of an active composite tissue allotransplantation (CTA) program. This article discusses the various criteria that are important in the selection of patients for CTA.     

Advances in composite tissue allograft transplantation as related to the hand and upper extremity

The clinical transplantation of composite tissue allografts (CTA) such as human hand or larynx is stimulating discussions among surgeons at national and international forums on the indications, ethical aspects, toxic effects of immunosuppression, and functional results of the first reported cases of unilateral and bilateral hand transplantation. This Clinical Perspective article presents the latest advances in clinical and experimental research related to the field of CTAs. The article presents the historic aspects of CTA, a broad view of the current state of composite tissue transplantation, the mechanism of allograft rejection, current experimental and clinical protocols, and, finally, the future prospects of the standard use of CTAs. It is clear that there is a substantial demand for routine use of CTAs but the treatment protocols need to be optimized and the functional outcomes need to be improved.     

The burned hand: a planned treatment program.

A planned treatment program for burned hands has been developed and was used in 72 burns of the dorsum of the hands. Treatment was individualized on the basis of whether hand burns were superficial or deep. In the former, there was evidence of spontaneous reepithelialization within 14 to 21 days. In the latter, immediate or delayed excision, followed by resurfacing with autografts was done. Both groups received topical antibiotic creaming, elevation, an exercise program as soon as they were able, and splinting of the burned hand in the antideformity position. Hypertrophic scars and unacceptable epithelium were excised when they interfered with function. Initially, this program allowed us to avoid unnecessary surgical procedures in 94% of the second-degree burns of the dorsum of the hand. The third-degree burned hand needed excision and autografting in 100% of the burned hands. This treatment program has as its goals: prevention of deformity by early motion and protection of the unburned and regenerating epithelium by creaming with topical antibiotic ointment.     

Work hardening: a mandate for hand therapy

Conditioning for return to work has become an integral part of the comprehensive hand rehabilitation program. Through experience and the development of guidelines, the practice of work hardening has matured. Skillful evaluation of the injured worker has enhanced the efficacy of work hardening programs. An understanding of program planning, implementation, and influential economic factors assist the work hardening team in creating and maintaining program excellence.     

Swine composite tissue allotransplant model for preclinical hand transplant studies

Our laboratory previously developed and used an orthotopic radial forelimb osteomyocutaneous flap in the pig as a preclinical composite tissue allograft (CTA) model. To ensure that it mimicked the clinical situation as closely as possible we developed this model taking many immunologic and reconstructive considerations into account. While our original pig CTA model was ideal for studying the methods of preventing skin, muscle, bone, vessel and nerve rejection, and systemic toxicity, it did not include specialized tissues/structures of a joint and digit. Therefore, we were unable to evaluate rejection of these specialized tissues and their functional properties. Recognizing the importance of assessing joint rejection and function in hand transplantation research we developed a new swine forelimb CTA model that included the animal's medial digit. The present study describes the anatomy and the transplantation technique used in this new preclinical CTA model. We transplanted a radial osteomyocutaneous flap that included the medial digit between two size- (17-21 kg) and age- (6-8-week) matched farm pigs. We removed the digit from the recipient pig's forelimb in continuity with a section of the radial bone and replaced it with the same structure transplanted from a donor pig. After transplantation, a full-length cast was placed on the recipient pig's operated limb and changes in flap color, temperature and the presence of edema were monitored continuously for 6 h, and then regularly at predetermined intervals over 4 days. No weight bearing restrictions were placed on the animal's operated limb. After 4 days, the animal was euthanized. Direct visual monitoring of the allograft during 4 days revealed it was viable with no signs of graft failure due to technical complications associated with the transplant procedure. Upon waking from anesthesia, the animal stood and wandered freely about its cage with no apparent difficulty. Based on the animal's high level of activity at this time, we concluded that the procedure caused it minimal morbidity. At 4 days after the operation, early signs of rejection (skin erythema and edema) were observed. By incorporating a digit into our original CTA pig forelimb model we have made it a better model for performing preclinical hand transplant studies. The added advantage of being able to assess methods of preventing rejection in the specialized joint/digital tissues (articular cartilage, digital flexor and extensor systems, the nail complex) and assess long-term function of these structures is important. The fact that the procedure does not cause major morbidity to the animal makes it possible to conduct long-term graft survival and functional studies.     

Naht und funktionelle Nachbehandlung von Beugesehnenverletzungen der Hand nach H. Kleinert

The restitution of flexor tendon injuries of the hand according to the tissue-sparing method and functional follow-up treatment indicated by H. Kleinert and his collaborators has become very important in the acute treatment of fresh injuries of the hand. Having applied this method in the treatment of 176 patients suffering from 346 separated flexor tendons in 235 fingers, we are now able to present the limited indication. The surgical proceeding and the complications occured are described, and the results found in the cases submitted to a follow-up examination (141 patients, 284 resutured flexor tendons in 194 fingers) are presented.     

Early postoperative mobilization of flexor tendon injuries using a modification of the Kleinert technique

The results of 99 flexor tendon repairs in all zones of injury in 36 patients are reported. Both superficialis and profundus tendons were repaired in all cases. Postoperatively patients were managed by an immediate active extension program using a modification of the Kleinert technique and physiotherapy. Results of the study are based on the Buck-Gramcko system of evaluation of flexor tendon repair. In the 70 digits that underwent operations, the results were excellent in 31% of the cases, good in 30%, fair in 20%, and poor in 19% of the cases. There were two tendon ruptures. This study corroborates evidence that early mobilization and hand therapy appear to play an important part in the postoperative management of flexor tendon injuries.     

University of Louisville experience and contributions to pediatric trauma care

Care of the injured patient has been a focal point of surgical training at the University of Louisville. Under the direction of Dr. Hiram C. Polk, Jr, M.D., the Trauma Service has received national recognition for excellence in patient care and surgical research. This experience has provided a foundation for further endeavors in trauma care by program graduates. Summaries of contributions to the peer-reviewed literature or to hospital programs by former trainees who specialized in pediatric surgery are presented. Topics include the treatment of pediatric solid-organ injury, pelvic fracture, pellet-gun injury, and caustic cutaneous burns. The impact of the pediatric Trauma Service at Kosair Children's Hospital in Louisville, KY, with an emphasis on compassionate care and the development of a bereavement intervention program, also is presented.     

La microchirurgie en traumatologie de la main

Résumé La microchirurgie apporte un progrès important au traitement primaire des plaies des mains. La microsuture des tendons fléchisseurs (Kleinert), la revascularisation par réparations artérielles et veineuses, la suture fasciculaire des nerfs sont des techniques fiables qui favorisent la cicatrisation et la récupération fonctionnelle, pourvu que la mobilisation précoce soit mise en oeuvre dans toute la mesure du possible et du raisonnable.

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Microsurgery in acute treatment of hand injuries

Summary Microsurgery has brought important progress in the primary treatment of wounds of the hand. Microsuture of flexor tendons (Kleinert), revascularization by arterial and venous repair and bundle suture of nerves are all proven techniques which favour healing and functional recovery, provided early mobilization is instituted whenever possible.

Présenté au Congrès de la SICOT à Kyoto — Octobre 1978     

Hand transplantation: comparisons and observations of the first four clinical cases

Twenty, 15, and 8 months after the first four successful human hand transplant procedures were performed in Lyon (France), Louisville (U. S.), and Guangzhou (China), the transplant teams convened in Louisville, Kentucky, to share their experiences at the Second International Symposium on Composite Tissue Allotransplantation. This article presents reconstructive and immunological data from these landmark procedures in tabular format, in an attempt to answer some key questions about early outcomes of clinical hand transplantation. On the basis of these data, the initial outcomes of the first four hand transplants are encouraging and warrant proceeding with additional hand transplantations.