Ethical challenges in vascularized composite allotransplantation of the lower extremity: lessons learned from hand transplantation and implications for the future

Abstract

Vascularized composite allotransplantation (VCA) is a novel surgical practice that involves the transplantation of multiple tissue types as a functional unit without the primary purpose of extending life. While VCA of the upper extremity is becoming increasingly accepted and performed, VCA of the lower extremity remains largely unexplored despite its acknowledged potential value. There are inherent ethical concerns surrounding VCA that are dominated by a conflict between the principles of beneficence and maleficence. The primary question is whether the quality-of-life benefits to the patient outweigh the risks associated with long-term immunosuppression for a non-lifesaving procedure. In addition, the ethical conversation involves concerns regarding informed consent, donor autonomy, patient privacy and public disclosure, patient selection, and unique considerations in the pediatric patient. Lower extremity VCA has additional ethical issues compared to upper extremity VCA, as current lower limb prostheses provide excellent, near baseline function that upper limb constructs have not yet been able to achieve. In this review, we discuss the ethical challenges of lower extremity VCA using available evidence for the upper extremity. We also compare ethical considerations of VCA of the extremity with other surgical alternatives to limb loss - namely, limb salvage and replantation - and address how the conversation may be altered with further advancements in immunosuppression and prosthetic technology.

Keywords

Vascularized composite allotransplantation (VCA) / lower extremity / ethics / limb salvage / replantation

References

[1] Ziegler-Graham K,Ephraim PL,Brookmeyer R.Estimating the prevalence of limb loss in the United States: 2005 to 2050.Arch Phys Med Rehabil2008;89:422-9

[2] Carty MJ,Talbot SG,Pribaz JJ.Attitudes regarding lower extremity allotransplantation among lower extremity amputees.Plast Reconstr Surg2014;134:1334-42

[3] Berke GM,Milani JR.Comparison of satisfaction with current prosthetic care in veterans and servicemembers from Vietnam and OIF/OEF conflicts with major traumatic limb loss.J Rehabil Res Dev2010;47:361-71

[4] Aaron RK,Ciombor DM.Horizons in prosthesis development for the restoration of limb function.J Am Acad Orthop Surg2006;14:S198-204

[5] Zuker R.Lower-extremity hindquarter transplantation in conjoined twins. Hand Transplantation. Springer: Milano. 2007. p. 435-41.

[6] Zuker RM,Alman B,Timoney N.First successful lower-extremity transplantation: technique and functional result.J Reconstr Microsurg2006;22:239-44

[7] Fattah A,Donner EJ,Alman BA.The first successful lower extremity transplantation: 6-year follow-up and implications for cortical plasticity.Am J Transplant2011;11:2762-7

[8] Cavadas PC,Carballeira A.Bilateral transfemoral lower extremity transplantation: result at 1 year.Am J Transplant2013;13:1343-9

[9] BBC. First double leg-transplant patient has legs amputated. Available from: https://www.bbc.com/news/health-22855670 [Last accessed on 24 Apr 2022]

[10] Cavadas PC,Blanes M.Primary central nervous system posttransplant lymphoproliferative disease in a bilateral transfemoral lower extremity transplantation recipient.Am J Transplant2015;15:2758-61

[11] Nasir S,Karaaltin MV.Lessons learned from the first quadruple extremity transplantation in the world.Ann Plast Surg2014;73:336-40

[12] CBS News. World’s first quadruple limb transplant fails at Turkish hospital. Available from: https://www.cbsnews.com/news/worlds-first-quadruple-limb-transplant-fails-at-turkish-hospital/ [Last accessed on 24 Apr 2022]

[13] Arudchelvam J,Wijesinghe N,Rajakrishna P.Trans-femoral lower limb transplantation in a Sri Lankan patient: a case report and surgical technique.Ceylon Med J2018;63:35-6

[14] Dubernard J,Herzberg G.Human hand allograft: report on first 6 months.The Lancet1999;353:1315-20

[15] Jones JW,Barker JH.Successful hand transplantation. One-year follow-up. Louisville hand transplant team.N Engl J Med2000;343:468-73

[16] Vascularized Composite Allograft Transplantation Committee. Implement the optn’s oversight of vascularized composite allografts (VCAs). Available from: https://optn.transplant.hrsa.gov/media/1118/05_vca_implementation.pdf [Last accessed on 24 Apr 2022]

[17] U.S. Department of Health and Human Services. Member Directory. Organ Procurement and Transplantation Network. Available from: https://optn.transplant.hrsa.gov/members/member-directory/ [Last accessed on 24 Apr 2022]

[18] Prentice M. Frameworks for organ distribution. Available from: https://optn.transplant.hrsa.gov/media/2565/geography_publiccomment_201808.pdf [Last accessed on 24 Apr 2022]

[19] Park SH,Kwon ST.Hand transplantation: current status and immunologic obstacles.Exp Clin Transplant2019;17:97-104

[20] Petruzzo P,Dubernard JM.The international registry on hand and composite tissue transplantation.Transplantation2010;90:1590-4

[21] Huchon L,Roy AC.Grasping objects by former amputees: the visuo-motor control of allografted hands.Restor Neurol Neurosci2016;34:615-33

[22] Carty MJ,Cavadas P,Talbot SG.The case for lower extremity allotransplantation.Plast Reconstr Surg2013;131:1272-7

[23] Veenstra KM,van der Eyken J.Quality of life in survivors with a Van Ness-Borggreve rotationplasty after bone tumour resection.J Surg Oncol2000;73:192-7

[24] SUNDERLAND S.Rate of regeneration in human peripheral nerves; analysis of the interval between injury and onset of recovery.Arch Neurol Psychiatry1947;58:251-95

[25] Gupta R,Uong J.Human motor endplate remodeling after traumatic nerve injury.J Neurosurg2020;1-8

[26] Gorantla VS,Nasir S,Davis MR.Lower extremity transplantation: concepts, challenges, and controversies. Springer: New York. 2017. p. 195-212.

[27] Kegel B,Burgess EM.Functional capabilities of lower extremity amputees.Arch Phys Med Rehabil1978;59:109-120

[28] Jablecki J,Patrzalek D,Chełmoński A.A detailed comparison of the functional outcome after midforearm replantations versus midforearm transplantation.Transplant Proc2009;41:513-6

[29] Petruzzo P,Kanitakis J.Outcomes after bilateral hand allotransplantation: a risk/benefit ratio analysis.Ann Surg2015;261:213-20

[30] Bramstedt KA.A lifesaving view of vascularized composite allotransplantation: patient experience of social death before and after face, hand, and larynx transplant.J Patient Exp2018;5:92-100 PMCID:PMC6022947

[31] Williams KD.Ostracism: The kiss of social death: ostracism: the kiss of social death.Social and Personality Psychology Compass2007;1:236-47

[32] Holt-Lunstad J,Baker M,Stephenson D.Loneliness and social isolation as risk factors for mortality: a meta-analytic review.Perspect Psychol Sci2015;10:227-37

[33] Caplan AL,Kahn J.Emerging ethical challenges raised by the evolution of vascularized composite allotransplantation.Transplantation2019;103:1240-6

[34] Salminger S,Sturma A,Aszmann OC.Hand transplantation versus hand prosthetics: pros and cons.Curr Surg Rep2016;4:8 PMCID:PMC4729794

[35] Salminger S,Roche AD.Functional and psychosocial outcomes of hand transplantation compared with prosthetic fitting in below-elbow amputees: a multicenter cohort study.PLoS One2016;11:e0162507 PMCID:PMC5010226

[36] Kubiak CA,Brandacher G.Prosthetic rehabilitation and vascularized composite allotransplantation following upper limb loss.Plast Reconstr Surg2019;143:1688-701

[37] Heineman J,Kiwanuka H.All hands on deck: hand replantation versus transplantation.SAGE Open Med2020;8:2050312120926351 PMCID:PMC7268554

[38] Petruzzo P,Lanzetta M.Report (2017) of the international registry on hand and composite tissue allotransplantation (IRHCTT).Curr Transplant Rep2017;4:294-303

[39] Shores JT,Lee WP.The current state of hand transplantation.J Hand Surg Am2011;36:1862-7

[40] Jabłecki J,Domanasiewicz A,Kaczmarzyk J.Unsuccessful attempt of forearm transplantation-case report.Ann Transplant2010;15:53-56

[41] Thaunat O,Dubois V,Petruzzo P.Immunopathology of rejection: do the rules of solid organ apply to vascularized composite allotransplantation?.Curr Opin Organ Transplant2015;20:596-601

[42] Elliott RM,Levin LS.Upper extremity transplantation: current concepts and challenges in an emerging field.Curr Rev Musculoskelet Med2014;7:83-8 PMCID:PMC4094126

[43] Chabas JF,Rao G.FK506 induces changes in muscle properties and promotes metabosensitive nerve fiber regeneration.J Neurotrauma2009;26:97-108

[44] Rustemeyer J,Keipert C.Administration of low-dose FK 506 accelerates histomorphometric regeneration and functional outcomes after allograft nerve repair in a rat model.J Craniomaxillofac Surg2010;38:134-40

[45] Rifkin WJ,Kantar RS.A Comparison of immunosuppression regimens in hand, face, and kidney transplantation.J Surg Res2021;258:17-22

[46] Jowsey-Gregoire SG,Morelon E,Petruzzo P.The Chauvet 2014 meeting report: psychiatric and psychosocial evaluation and outcomes of upper extremity grafted patients.Transplantation2016;100:1453-9

[47] Sifferlin A. I can do absolutely nothing. The first American with a double hand transplant wants them removed. Available from: https://time.com/4419959/double-hand-transplant-surgery/ [Last accessed on 24 Apr 2022]

[48] Dobbs D. The devastating allure of medical miracles. Available from: https://www.wired.com/story/devastating-allure-of-medical-miracles/ [Last accessed on 24 Apr 2022]

[49] Kumnig M.Key psychosocial challenges in vascularized composite allotransplantation.World J Transplant2016;6:91-102 PMCID:PMC4801807

[50] Smith PJ.Psychosocial dimensions of hand transplantation: lessons learned from solid organ transplantation.Curr Opin Organ Transplant2019;24:705-13

[51] Dorante MI,Talbot SG.Should a Caregiver’s QoL be considered in decisions about whether a patient has an experimental double-hand transplant?.AMA J Ethics2019;21:E943-952

[52] Pierrie SN,Loeffler BJ.Current concepts in upper-extremity amputation.J Hand Surg Am2018;43:657-67

[53] Teven CM.Plastic surgery’s contributions to surgical ethics.AMA J Ethics2018;20:349-56

[54] Lange MM,Dodds S.Vulnerability in research ethics: a way forward.Bioethics2013;27:333-40

[55] Majzoub RK,Grossi F,Banis JC.Investigation of risk acceptance in hand transplantation.J Hand Surg Am2006;31:295-302

[56] Guidance to Organ Procurement Programs (OPOs) for VCA Deceased Donor Authorization. Available from: https://optn.transplant.hrsa.gov/media/1137/vca_donor_guidance.pdf [Last accessed on 24 Apr 2022]

[57] National Conference of Commissioners on Uniform State Laws. Revise uniform anatomical gift act. Available from: https://www.donornetworkwest.org/wp-content/uploads/uaga_final_aug09.pdf [Last accessed on 24 Apr 2022]

[58] Pennsylvania General Assembly. Chapter 86: anatomical gifts. Available from: https://www.legis.state.pa.us/WU01/LI/LI/CT/HTM/20/00.086..HTM [Last accessed on 24 Apr 2022]

[59] Rahmel A.Vascularized composite allografts: procurement, allocation, and implementation.Curr Transplant Rep2014;1:173-82 PMCID:PMC4405348

[60] Iltis AS.Ethical issues in pediatric VCA.Curr Transplant Rep2017;4:311-319

[61] Rodrigue JR,Fleishman A.Vascularized composite allograft donation and transplantation: a survey of public attitudes in the United States.Am J Transplant2017;17:2687-95

[62] Magill G,Plock JA,Gorantla VS.Brocher Working Group on VCAExisting and evolving bioethical dilemmas, challenges, and controversies in vascularized composite allotransplantation: an international perspective from the brocher bioethics working group.Transplantation2019;103:1746-51

[63] Henderson ML,Fisher JS.Social media and organ donation: Ethically navigating the next frontier.Am J Transplant2017;17:2803-9

[64] Vrakas G,Giele H.Vascularized composite allotransplantation. p. 373-97.

[65] Gorantla VS,Davis MR.Reconstructive transplantation: evolution, experience, ethics, and emerging concepts. Springer: New York. 2017. p.539-52.

[66] Shores JT.Recipient screening and selection: who is the right candidate for hand transplantation.Hand Clin2011;27:539-43, x

[67] Siemionow MZ.Institutional review board-based recommendations for medical institutions pursuing protocol approval for facial transplantation.Plast Reconstr Surg2010;126:1232-9

[68] McQuinn MW,Parent B.Self-inflicted gunshot wound as a consideration in the patient selection process for facial transplantation.Camb Q Healthc Ethics2019;28:450-62

[69] McDiarmid SV.Vascularized composite allotransplantation in children: what we can learn from solid organ transplantation.Curr Opin Organ Transplant2018;23:605-14

[70] Amaral S,Levy TJ.18-month outcomes of heterologous bilateral hand transplantation in a child: a case report.2017;1:35-44

[71] Azoury SC,Kimia R.Four-year follow-up of the world’s first pediatric bilateral hand-forearm transplants: do they grow as expected?.Plast Reconstr Surg2020;146:1325-9

[72] Shaul R,Flynn J,Wright L.Ethical issues in pediatric vascularized composite allotransplantation.Ethical Issues in Pediatric Organ Transplantation2016;66:169-91

[73] Doumit G,Rampazzo A,Siemionow MZ.Pediatric vascularized composite allotransplantation.Ann Plast Surg2014;73:445-50

[74] Malik S,Cochat P.Overview of pediatric organ transplantation: current opinion and future perspectives on immunosuppression.Curr Opin Organ Transplant2015;20:527-35

[75] Amaral S.Pediatric and congenital hand transplantation.Curr Opin Organ Transplant2017;22:477-83

[76] Ruebner RL,Denburg MR,Furth SL.End-stage kidney disease after pediatric nonrenal solid organ transplantation.Pediatrics2013;132:e1319-26 PMCID:PMC3813394

[77] Yazigi NA.Adherence and the pediatric transplant patient.Semin Pediatr Surg2017;26:267-71

[78] Shemesh E,Arnon R,Kerkar N.Adherence to medical recommendations and transition to adult services in pediatric transplant recipients.Curr Opin Organ Transplant2010;15:288-92 PMCID:PMC3101800

[79] Fredericks EM,Aujoulat I,Wray J.Post-transplant adjustment--the later years.Pediatr Transplant2014;18:675-88

[80] Azeka E,Fregni F.Clinical research in pediatric organ transplantation.Clinics2014;69:73-5 PMCID:PMC3884155

[81] COMMITTEE ON BIOETHICS.Informed consent in decision-making in pediatric practice.Pediatrics2016;138:e20161484

[82] Barfield RC.Informed consent in pediatric clinical trials.Curr Opin Pediatr2005;17:20-4

[83] Zubairi AJ.Long term follow-up of a successful lower limb replantation in a 3-year-old child.Case Rep Orthop2015;2015:425376 PMCID:PMC4398936

[84] Li XL,Liu F,Liang DS.Successful lower limb replantation of knee-level amputation in a child: a case report.J Foot Ankle Surg2020;59:427-30

[85] Fufa DT,Lin YT,Lin CH.Survival and secondary surgery following lower extremity replantation.J Reconstr Microsurg2014;30:419-26

[86] Fang J,Dou H.Crossover replantation after bilateral traumatic lower limb amputations: a case report.J Med Case Rep2012;6:218 PMCID:PMC3419122

[87] Bosma NH,Eberlin KR.Lower limb replantation after guillotine amputation: a 29-year follow-up.J Reconstr Microsurg2015;31:681-3

[88] Yu G,Guo S,Huang JH.Successful replantation of both lower legs in a 41-year-old man.Chin J Traumatol2011;14:250-252

[89] Tudosie A,Cinteza D.Rehabilitation in a patient with replantation of amputated distal leg.Maedica (Bucur)2011;6:36-44. PMCID:PMC3150028

[90] Cavadas PC,Ibáñez J,Nthumba P.Infrapopliteal lower extremity replantation.Plast Reconstr Surg2009;124:532-9

[91] Ricketts S,Breidahl A.Eleven-year follow-up of cross-leg replantation for traumatic bilateral amputation.J Reconstr Microsurg2009;25:111-5

[92] Bosse MJ,Kellam JF.An analysis of outcomes of reconstruction or amputation after leg-threatening injuries..N Engl J Med2002;347:1924-31

[93] MacKenzie EJ.Factors influencing outcome following limb-threatening lower limb trauma: lessons learned from the Lower Extremity Assessment Project (LEAP).J Am Acad Orthop Surg2006;14:S205-10

[94] MacKenzie EJ,Castillo RC.Functional outcomes following trauma-related lower-extremity amputation.J Bone Joint Surg Am2004;86:1636-45

[95] MacKenzie EJ,Pollak AN.Long-term persistence of disability following severe lower-limb trauma. Results of a seven-year follow-up.J Bone Joint Surg Am2005;87:1801-9

[96] McCarthy ML,Edwin D,Castillo RC.LEAP study groupPsychological distress associated with severe lower-limb injury.J Bone Joint Surg Am2003;85:1689-97

[97] Smith JJ,Swiontkowski MF,Mackenzie E.LEAP Study GroupFunctional outcome of bilateral limb threatening: lower extremity injuries at two years postinjury.J Orthop Trauma2005;19:249-53

[98] MacKenzie EJ,Pollak AN.The major extremity trauma research consortium: an overview.J Orthop Trauma2017;31 Suppl 1:S1

[99] Extremity Trauma Research Consortium (METRC). Outcomes following severe distal tibial, ankle, and/or mid/hindfoot trauma: comparison of limb salvage and transtibial amputation (OUTLET).J Bone Joint Surg Am2021;103:1588-97

[100] Sugun TS,Ada S.Long-term results of major upper extremity replantations..Acta Orthop Traumatol Turc2009;43:206-13

[101] Pei G,Gu L.A report of 15 hand allotransplantations in 12 patients and their outcomes in China.Transplantation2012;94:1052-9

[102] Tark KC,Lee YH.Replantation and revascularization of hands: Clinical analysis and functional results of 261 cases.The Journal of Hand Surgery1989;14:17-27

[103] Landin L,Casado-Sanchez C.Outcomes with respect to disabilities of the upper limb after hand allograft transplantation: a systematic review.Transpl Int2012;25:424-32

[104] Lanzetta M.A Comprehensive functional score system in hand transplantation. 2007.

[105] Jensen SE,Bill A.Quality of life considerations in upper limb transplantation: review and future directions.J Hand Surg Am2012;37:2126-35

[106] Bachmann D. Quality of life in hand transplant patients. In: Hand Transplantation.Available from: http://eknygos.lsmuni.lt/springer/673/Part%209/363-366.pdf [Last accessed on 24 Apr 2022]

[107] O’Toole RV,Pollak AN,Bosse MJ.Determinants of patient satisfaction after severe lower-extremity injuries..J Bone Joint Surg Am2008;90:1206-11

[108] Scott FA,Boswick JA Jr.Recovery of function following replantation and revascularization of amputated hand parts.J Trauma1981;21:204-14

[109] Petruzzo P.The international registry on hand and composite tissue allotransplantation.Clin Transpl2011;247-253

[110] Frey SH,Smith JC,Breidenbach WC.Chronically deafferented sensory cortex recovers a grossly typical organization after allogenic hand transplantation.Curr Biol2008;18:1530-4 PMCID:PMC2604120

[111] Pribaz JJ,Barrall D.Double fillet of foot free flaps for emergency leg and hand coverage with ultimate great toe to thumb transfer.Plast Reconstr Surg1993;91:1151-3

[112] Battiston B,Pontini I.Lower limb replantations: indications and a new scoring system.Microsurgery2002;22:187-92

[113] Kinsley SE,Lape EC.Perceived success in upper-extremity vascularized composite allotransplantation: a qualitative study.J Hand Surg Am2021;46:711.e1-711.e35

[114] Wright TW,Wood MB.Prosthetic usage in major upper extremity amputations.The Journal of Hand Surgery1995;20:619-22

[115] Pezzin LE,Mackenzie EJ,Rossbach P.Use and satisfaction with prosthetic limb devices and related services.Arch Phys Med Rehabil2004;85:723-9

[116] Legro MW,del Aguila M.Issues of importance reported by persons with lower limb amputations and prostheses.J Rehabil Res Dev1999;36:155-163

[117] Biddiss EA.Upper limb prosthesis use and abandonment: a survey of the last 25 years.Prosthet Orthot Int2007;31:236-57

[118] Baars EC,Dijkstra PU.Prosthesis satisfaction in lower limb amputees: A systematic review of associated factors and questionnaires.Medicine (Baltimore)2018;97:e12296 PMCID:PMC6181602

[119] Hobusch GM,Brånemark R.Advanced techniques in amputation surgery and prosthetic technology in the lower extremity.EFORT Open Rev2020;5:724-41 PMCID:PMC7608512

[120] El-Sayed AM,Abu Osman NA.Technology efficacy in active prosthetic knees for transfemoral amputees: a quantitative evaluation.ScientificWorldJournal2014;2014:297431 PMCID:PMC4119677

[121] Laferrier JZ.Advances in lower-limb prosthetic technology.Phys Med Rehabil Clin N Am2010;21:87-110

[122] Kuiken TA,Lock BA,Dewald JP.Redirection of cutaneous sensation from the hand to the chest skin of human amputees with targeted reinnervation.Proc Natl Acad Sci U S A2007;104:20061-6 PMCID:PMC2148422

[123] Sensinger JW,Kuiken TA.Examination of force discrimination in human upper limb amputees with reinnervated limb sensation following peripheral nerve transfer.IEEE Trans Neural Syst Rehabil Eng2009;17:438-44 PMCID:PMC3025706

[124] Gart MS,Dumanian GA.Targeted muscle reinnervation in the upper extremity amputee: a technical roadmap.J Hand Surg Am2015;40:1877-88

[125] Chang BL,Attinger CE.Targeted muscle reinnervation improves pain and ambulation outcomes in highly comorbid amputees.Plast Reconstr Surg2021;148:376-86

[126] Hargrove LJ,Simon AM.Intuitive control of a powered prosthetic leg during ambulation: a randomized clinical trial.JAMA2015;313:2244-52

[127] Park K,Lee KH.Development and performance verification of a motorized prosthetic leg for stair walking.Appl Bionics Biomech2020;2020:8872362 PMCID:PMC7609156

[128] Young AJ,Hargrove LJ.Analysis of using EMG and mechanical sensors to enhance intent recognition in powered lower limb prostheses.J Neural Eng2014;11:056021

[129] Hebert JS,Stiegelmar R.Osseointegration for lower-limb amputation: a systematic review of clinical outcomes.JBJS Rev2017;5:e10

[130] Muderis M, Khemka A, Lord SJ, Van de Meent H, Frölke JP. Safety of osseointegrated implants for transfemoral amputees: a two-center prospective cohort study.J Bone Joint Surg Am2016;98:900-9

[131] Lundberg M,Bullington J.My prosthesis as a part of me: a qualitative analysis of living with an osseointegrated prosthetic limb.Prosthet Orthot Int2011;35:207-14

[132] Tsakiris M,James D.Hands only illusion: multisensory integration elicits sense of ownership for body parts but not for non-corporeal objects.Exp Brain Res2010;204:343-52

[133] Bekrater-Bodmann R.Factors associated with prosthesis embodiment and its importance for prosthetic satisfaction in lower limb amputees.Front Neurorobot2020;14:604376 PMCID:PMC7843383

[134] Healy A,Eddison N.A scoping literature review of studies assessing effectiveness and cost-effectiveness of prosthetic and orthotic interventions.Disabil Rehabil Assist Technol2020;15:60-6

[135] Fryer M,Khalifian S.Exploring cell-based tolerance strategies for hand and face transplantation.Expert Rev Clin Immunol2015;11:1189-204

[136] Leonard DA,McGrouther DA.Induction of tolerance of vascularized composite allografts.Transplantation2013;95:403-9

[137] Scott LR,Stephen E.Anesthetic management in upper extremity transplantation.2012;115:678-88

[138] Brandacher G,Schneeberger S.Minimizing immunosuppression in hand transplantation.Expert Rev Clin Immunol2012;8:673-83; quiz 684

[139] Bertrand AA,Otake LR.Changing attitudes toward hand allotransplantation among North American hand surgeons.Ann Plast Surg2014;72 Suppl 1:S56-60

[140] Mathes DW,Ploplys E.A survey of north american hand surgeons on their current attitudes toward hand transplantation.J Hand Surg Am2009;34:808-14