Upper Limb Reconstructive Transplantation in Military Recipients: Summary of World Experience

6 Journal of the Royal Naval Medical Service 2018; 104(1) Upper limb reconstructive transplantation in military recipients: summary of world experience C A Fries, H L Stark, D Tuder, S Iyer, V S Gorantla, M R Davis, R F Rickard

Abstract

Lessons from conflict have contributed to military medical advances which have significantly improved the survivability of critically injured servicemen and women. However, survival following such severe combat polytrauma is often associated with devastating tissue loss and functional deficits that challenge conventional reconstruction. Despite recent advances, upper extremity prosthetic alternatives lack the fidelity to restore the complex intrinsic and sensory function of the human hand. Up- per Limb Reconstructive Transplantation, or Vascularised Composite Allotransplantation (VCA), is currently an experimental procedure offering superior anatomical and functional outcomes compared to prostheses. Military candidates for VCA usually enjoy high pre-morbid fitness, mental health resilience and support, and relatively rich provision of rehabilitation. However, co-morbidities of polytrauma, such as traumatic brain injury and post-traumatic stress dis- order, may have an impact on outcomes. Since 1998, over 120 upper limb transplants have been performed worldwide. Of these, six have been performed on servicemen and women across three continents. The morbidity and mortality associated with the requirement for lifelong immunosuppression, however, continues to skew the risk-benefit considerations of these promising procedures when compared to prostheses. Thus, although the technical surgical feasibility of upper limb and other VCA such as face, abdominal wall, uterus and penis transplants has been established over the past decade, these procedures remain restricted to recipients fulfilling stringent inclusion criteria. We review the current state of VCA in military recipients, and summarise ongoing collaborative VCA research conducted by British and American military medical teams.

Fries C A, Stark H L, Tuder D, et al. J R Nav Med Serv 2018;104(1):6–11

Introduction Vascularised composite allotransplantation (VCA) is the in- novative frontier of reconstructive surgery. Anatomical and From 2003 to 2012, the survivability of military wounds sus- functional restoration of even massive tissue loss can be ac- tained by British service personnel injured in Iraq and Afghan- complished with identical tissues from deceased donors. In istan improved year on year. In their elegant study Penn-Bar- the global experience of over 120 upper limb VCA, function- well et al. showed that the New Injury Severity Score (NISS) al, immunological and graft survival outcomes have ranged associated with a 50% chance of survival rose from 32 to 60 widely, from encouraging to poor. The primary risk-benefit during this period.1 The reason for success was multifactorial, consideration for these VCA is influenced strongly by the including incremental improvements in the military chain of morbidity and toxicity of multiple, high dose immunosup- care from the point of injury on the battlefield to definitive treat- pressive drugs required for graft maintenance. These risks ment at the Royal Centre for Defence Medicine in Birmingham. continue to limit the clinical application and benefits of these Improvements in techniques, tactics and procedures as well as life-enhancing but not life-saving procedures. At the time of equipment, notably in the universal provision of body armour this publication, six servicemen or women in the USA, In- and its evolution during the conflicts, also played a significant dia and Poland have undergone upper limb transplantation in role. Despite the best body armour, the limbs, head and neck, the context of blast injury. Four cases were bilateral and two and pelvis were exposed to devastating injury. The rates of am- unilateral. In this paper, we review the published literature putation and significant maxillofacial trauma are higher in this on these cases and summarise current military research and group of survivors compared to those of previous conflicts.2,3 future direction for VCA. Despite optimal reconstructive surgical approaches, rehabilitation therapy and modern prosthetics, functional outcomes are Military Cases highly unlikely to return to pre-injury levels. An imperative therefore exists for military medicine to advance reconstructive Table 1 summarises the military cases that have been per- surgery in tandem with advances in resuscitative care. formed to date. Original articles 7

Date Patient Indication Operation Centre Remarks

Mar 2009 24 year old male Unilateral hand loss Unilateral hand VCA University of (blast injury) Pittsburgh Medical Center, USA Feb 2010 50 year old female Unilateral hand loss, Unilateral hand VCA Wilford Hall letter bomb Ambulatory Surgical Center San Antonio, TX, USA Jun 2010 31 year old male Bilateral hand loss, Bilateral hand VCA Trzebnica, Poland Female donor to training accident with male recipient explosive Dec 2012 26 year old male Bilateral hand loss, Bilateral hand VCA Johns Hopkins, Female donor to blast Baltimore, MD, USA male recipient May 2015 30 year old male Bilateral hand loss, Bilateral hand VCA Amrita Institute of blast, EOD Medical Sciences, Kochi, India Aug 2016 31 year old male Bilateral hand loss, Bilateral hand VCA Brigham and Women’s blast AFG Hospital, Boston, MA, USA

Table 1: military cases of VCA performed to date.

Case 1 Case 2 The first serviceman to receive a hand transplant in the USA Case two describes the first female hand allotransplantation was a 24-year-old Marine Corporal who had served two tours performed in the USA and the first to be conducted at a De- in Iraq. The patient had suffered a blast injury to the right hand fence establishment. The patient, a USAF master sergeant, in 2005 during military exercises at the Marine Corps base had sustained a traumatic left wrist disarticulation as the re- in Quantico, Virginia. He underwent informed consent after sult of a parcel bomb explosion within the continental Unit- exhaustive screening and comprehensive psychosocial assess- ed States. At the time of injury she was 50 years old, left ment. The donor was matched for limb size, skin colour, tone hand dominant and otherwise fit and well. She had -subse and gender. He received alemtuzumab induction with methyl- quently undergone numerous revision surgeries and multiple prednisolone. Transplantation was performed in March 2009 prosthetic trials without a satisfactory outcome. In February and tacrolimus monotherapy was commenced. The regimen 2010, after extensive medical and psychological screening, also included a novel cell-based immunomodulatory protocol, she underwent transplantation at the Wilford Hall Ambulato- the Pittsburgh protocol, that incorporates donor bone marrow ry Surgical Centre, San Antonio, USA. The donor hand was a (BM) infusion.4 Cryopreserved whole donor BM from nine skin colour-matched, CMV positive, deceased female donor. vertebral bodies was infused on day 14. The patient was mon- The procedure took 9.5 hours with an ischaemia time of 3.5 itored for clinical, functional and immunological outcomes hours. Following induction immunotherapy with thymoglob- with routine and specialised assays. The degree of motor and ulin and solumedrol, she was managed with a maintenance sensory return correlated with time after transplantation and regimen of tacrolimus, prednisolone and mycophenolate level of amputation. Immunomonitoring revealed transient mofetil. In the six years of follow up to date she has been moderate donor-specific antibodies, adequate immunocom- successfully treated for 11 episodes of acute rejection. In ad- petence and no immunological chimerism. High-resolution dition, she has suffered three episodes of CMV re-activation ultrasound demonstrated patent vessels with no luminal nar- and two episodes of acute kidney injury. Functionally, she rowing or occlusion. Side effects were few, with no system- now enjoys two-point discrimination in all fingers of 11mm, ic infectious or other serious complications. The patient was and is sensitive to hot and cold stimuli. She has developed satisfied with transplant-related quality of life outcomes and fixed flexion deformities of the PIPJ (45 degrees index and gained significant independence with personal and vocation- middle, 90 degrees ring and little finger) and has MCPJ range al abilities. However, at year two, he became non-compliant of motion of 0-90 degrees. Her pre-operative DASH score with medication and physician recommendations. He suffered was 37.5, post-operatively improving to 17.5. The patient is multiple episodes of recurrent steroid and antibody-resistant very happy with her outcome and has returned to work and rejection and eventually chronic rejection necessitated the am- horseback riding. She has required one additional revision putation of the allograft three years after transplantation. procedure. 8 Journal of the Royal Naval Medical Service 2018; 104(1)

Case 3 Case 6 Case 3 was 31 at the time of his injury. He was a Polish Special Case 6 was a US Marine Sergeant, injured by an improvised Forces soldier and was injured in a training accident, saving a explosive device whilst serving in Afghanistan. He was 25 at young recruit from a bomb that then exploded in his hands. He the time of injury in 2010 and suffered quadruple limb loss. lost his left hand and the thumb and two fingers from his right. He underwent bilateral hand transplantation six years later, in He underwent bilateral hand transplantation three years later Baltimore, USA. The operation took 14 hours. At present there in Trzebnica, Poland. The operation took 17 hours. At present are no published follow up data (see Figure 2). there is no information published on his ongoing progress. Discussion Case 4 The complex intrinsic motor and sensory function of the hu- Case 4 was a US Army Sergeant and the first US soldier to sur- man hand is unique and fundamental to our interaction with vive quadruple traumatic limb loss. In 2008, at the age of 22, our environment. A review of all Royal Naval Service person- he was injured by a roadside bomb in Iraq. Four years later, in nel evaluated by a Naval Service Medical Board of Survey December 2012, he underwent bilateral hand transplantation following an injury in Iraq or Afghanistan showed a retention in Baltimore, USA. The procedure took 13 hours. Immuno- in service rate of 67%. Subgroup analysis revealed a dispro- logical tolerance was induced through the Pittsburgh protocol portionately high rate of medical discharge in cases of upper as with the first case. Eighteen months following his opera- limb injury, illustrating the vital sensory and prehensile function, he was able to perform pull-ups, press-ups and drive an tion that the hands provide.5 Functional restoration of an am- adapted car. putated hand to pre-injury levels is impossible using conventional techniques. The most advanced upper limb prostheses, Case 5 in contrast to those for the lower limb, are unable to replicate Case 5 was an Afghan Army Captain who, at the age of 27, the delicate tactile feedback or the range and delicate motor was injured when defusing a mine in Afghanistan. He lost control of the human hand. It is well documented that few up- both his hands, but suffered no other injuries. He received per limb amputees use their prosthetic regularly; this has also a bilateral hand transplant in Kochi, India in May 2015, the been demonstrated in the military population.6 second double hand transplant to be carried out in India. He was 30 years old at the time of surgery. The operation took The most common VCA are upper limb or craniofacial 15 hours. He underwent thymoglobulin induction followed by transplants.7 Other composite tissues to be transplanted triple drug maintenance immunosuppression. He returned to have included abdominal wall (in the context of achieving Afghanistan at the end of one year to resume service in the abdominal wall closure in small bowel transplantation), Army. At that time, he had a grip strength of 18 kg in the right uterus and penis.8 Five live pregnancies have been attrib- hand and 10 kg in the left hand. He had achieved a mean static uted to uterine transplant recipients in Sweden.9 A sub-set 2PD of 8 mm in the left hand and 6 mm in the right hand. His of VCA patients exist who have already undergone a solid DASH score had improved from 86 to 9 (see Figure 1). organ transplant, and are therefore already taking systemic

Figure 1: A 30-year-old Afghan military captain, Abdul Rahim from Kandahar, who lost his hands while defusing mines in the war torn country, now has two Indian hands - thanks to a successful transplant carried out at an institute in Kochi, India in May 2015 (image provided by Dr Gorantla). Original articles 9

Figure 2: US Marine Sgt John Peck, 31, became a quadruple amputee after being wounded in combat in Afghanistan in 2010. He had a double transplant in October 2016 in BWH (images provided by Dr Gorantla).

immunosuppression. In these cases, the ethical dilemma re- however, successful VCA procedures have been performed garding the use of immunosuppression for a non-lifesaving in victims of blast, gunshot injuries and burns, as well as indication does not apply. The most high profile of these non-traumatic indications including neoplasia and necrotising cases is the world’s first paediatric VCA; a bilateral hand infections. transplant performed on a child who was eight years of age at the time of transplantation.10 Other cases in solid organ Worldwide, to the end of 2016, three civilian VCA patients transplant patients yet to be reported in the literature include had died as a direct result of the immunosuppression asso- those of scalp and anterior neck.11 ciated with their transplants.18 Two combined hand and face transplant patients in the immediate post-operative phase, and Hand VCA recipients have demonstrated good functional out- in 2016 the world’s first face transplant recipient from 2005, comes with return of sensation and intrinsic motor function. succumbed following complications of surgery to manage ma- Disability of the Arm, Shoulder and Hand (DASH) scores lignancies resulting from immunosuppression. Further cases have been shown to be significantly higher than pre-operative of treatment failure and re-amputation have occurred but have levels and in comparison to prosthetic use.12-15 Face transplant not been widely publicised. It is for this reason that many spe- recipients have also reported improved quality of life scores cialists in the field currently advocate more research before after transplantation.16 advancing further with clinical adoption.

Wordsworth et al., in their discussion of the implications of Current research and future prospects VCA for British military patients, noted its position in the Since 2012, collaborative research into VCA immunology spectrum of developing technologies; interfacing reconstruc- has been ongoing between the United States Army Institute tive surgery, bio-engineering, and prosthetics including tar- of Surgical Research in San Antonio, Texas, and the Academ- geted muscle re-innervation.17 Significant reservations exist ic Department of Military Surgery and Trauma at the Royal about the widespread use of VCA due to the risks alluded Centre for Defence Medicine. The collaboration has focused to above; these led to the US Armed Forces establishing the on delivering immunomodulation within VCA grafts to min- Tri-Service Transplant Advisory Board at the Uniformed Ser- imise systemic immunosuppression. Translational large ani- vices University of the Health Sciences in Bethesda, Maryland mal VCA models have been developed to evaluate strategies to oversee all cases of VCA proposed for American service involving amelioration of the ischaemia reperfusion injury to members. However, the US Armed Forces have been heavily prevent acute rejection indirectly, and local graft treatments involved in funding pre-clinical VCA research and both civil- with a directly immunomodulatory effect.19-23 Success has ian and military clinical VCA cases. been achieved at a pre-clinical level and ongoing efforts are directed at clinical translation. Possible concerns for military application have included the suitability of patients who have suffered blast-type - in Conclusion jury patterns with extensive zones of injury, multiple blood transfusions leading to immunological sensitisation, and the The field of VCA has developed to a stage where, having possibility of latent infections or delayed systemic inflamma- achieved technical successes, the focus has shifted to opti- tory response syndromes. The latter phenomenon has been mising long-term outcomes and function, and most critically witnessed in delayed reconstruction cases of such severely to reducing the burden of the required immunosuppression. injured soldiers. More importantly, the signature collateral in- Some authors have suggested that VCA transplantation for juries of blast polytrauma, such as PTSD or TBI, could make certain indications is already the standard of care.24 Regu- these patients poor candidates for VCA. In the civilian setting lar correlation of clinical and immunopathological findings 10 Journal of the Royal Naval Medical Service 2018; 104(1) can help to fine-tune immunosuppression. Implementation applicability of this reconstructive modality. Longer-term of novel protocols that aim to minimise long term drug-de- follow up, with more widely agreed functional, immuno- livered immunosuppression could improve the risk benefit logical and graft survival outcome measures, will provide ratio by minimising the number, dose and duration of drugs greater insight into the indications and utility of upper limb used. This would, in turn, improve the safety and widen the VCA.

References

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Authors

Surgeon Lieutenant Commander C A Fries Royal Navy, Plastic Surgery Registrar, Institute of Naval Medicine, Alverstoke, Gosport, UK. [email protected] Miss H L Stark, Plastic Surgery Registrar, Royal Victoria Hospital, Newcastle Upon Tyne Hospitals, Newcastle Upon Tyne, UK. Colonel (S) D Tuder, Consultant Orthopaedic Surgeon, United States Air Force (Reserve), San Antonio, Texas, USA. Original articles 11

Professor S Iyer, Professor and Chairman, Plastic and Reconstructive Surgery, Head and Neck Surgery and Oncology, Amrita Institute of Medical Sciences, Kochi, Kerala, India. Dr V S Gorantla, Associate Professor of Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

Colonel M R Davis, Director, US Combat Casualty Care Research Program, Medical Research and Materiel Command, Washington DC, USA.

Surgeon Captain R F Rickard Royal Navy, Defence Professor of Surgery, Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, UK.