Craniomaxillofacial trauma management in austere and war zone environments - A role for composite tissue allotransplantation?

Summary

Facial composite tissue allotransplantation (CTA) is a powerful reconstructive option in cases of extensive severe facial injury and tissue loss. Despite the risk of allograft rejection and the post-operative need for lifelong immunosuppression, facial CTA can be used to restore the normal structural appearance and function of the face. Areas of socioeconomic deprivation and armed conflict zones have a high preponderance of patients with facial burns and other severe injuries. However, these regions often also suffer from lack of resources, expert surgical care and limited facilities. The purpose of this manuscript is to provide a comprehensive review of key principles relevant to facial CTA and their potential applicability in such austere environments. We present a concise literature review of the surgical and immunological basis of facial CTA aimed at the plastic surgery readership, as well as issues surrounding organ transplantations in low- and middle- income countries. We then consider the particular challenges posed by austere settings and countries of active armed conflict and discuss how these may impact the suitability of facial CTA for treating severe facial injuries in these circumstances. Facial CTA is recognised as giving huge benefits for patients with severe facial defects with potentially superior results compared with conventional autograft techniques. Its performance in austere settings is limited by scarce resources and increased pre-, intra- and post- operative risks. However, a case can be made for its use even in these more challenging situations when general organ transplantation compliance and expertise input have been addressed.

Introduction

Facial defects as a result of burns, trauma or congenital anomalies are a major cause of morbidity and mortality worldwide, with particular prevalence and severity in areas of socioeconomic deprivation and civil unrest.¹ The complexity of facial anatomy and the unique mode by which the structural and functional subunits of the face come together to establish one’s identity makes facial reconstruction a challenging but fascinating field of medicine and surgery. Though effective, traditional reconstructive methods are not always sufficient to restore the normal structural appearance and function of the face.

Facial burns result in functional and aesthetic complications that pose significant challenges in reconstructive surgery and necessitate the application of various steps of the reconstructive ladder. Management of limited burns involves skin grafting techniques followed by the use of dressings, pressure garments, splints, silicone gel and/or steroid injections to prevent scarring and contractures.^2-4 However, with increasing depth and surface area of the burn, to restore the normal appearance and basic motor/sensory actions of the face, flap procedures are performed. Burns that do not cross aesthetic units of the face can be managed with local flap techniques such as z-plasty, transposition,⁵ square⁶ or propeller flaps.⁷ However, tissue adjacent to the defect is usually also burned and large lesions cannot be covered using local flaps. The mainstay of managing extensive, severe facial burns is free-tissue transfer, including but not limited to: anterolateral thigh,^8,9 medial calf,¹⁰ deltopectoral,¹¹ scapular/parascapular^12,13 and radial forearm flaps.¹⁴ Advances in free-tissue transfer techniques (e.g. pre-expansion,¹⁵ pre-fabrication,^16,17 pre-lamination,¹⁸ “super-thin” flaps^19,20 and chimeric flaps²¹) are improving outcomes for facial burn patients by enabling the use of thinner flaps, more complementary to the recipient site. However, many patients continue to look deformed and undergo multiple flap debulking or sculpting procedures with little improvement.²² Composite tissue allotransplantation (CTA) is the surgical transfer of an allograft made up of heterogenous cadaveric tissues (including skin, fat, muscle, nerves, bone, cartilage, ligaments and bone marrow).

It is used to manage severely injured patients, enabling structural, functional and aesthetic restoration of major tissue defects.²³ Although thought to elicit a stronger immune response compared with solid organ transplantation, the concept of CTA pre-dates that of solid organ transplantation. “The Miracle of the Moor’s (Black) Leg” recounts the work of Cosmas and Damian, twin brothers and the patron saints of medicine, who used the leg of a recently deceased Ethiopian Moor to replace a sleeping man’s cancerous leg in 348 AD.²⁴ During the Renaissance, Gaspare Tagliacozzi successfully reconstructed a nose by autologous transplantation using the arm but encountered difficulties when attempting to transfer the nose from one individual to another.²⁵ Though allotransplantation was later successfully performed on animals throughout the 1800s,^26,27 initial CTA attempts in humans led to rejection within the first few months - the first successful human hand transplant was not performed until 1998.²⁸ CTA of the hands, vascularised knee, abdominal wall, flexor tendon apparatus, larynx, tongue, face and nerves have since been successfully performed.²⁹

Facial composite tissue allotransplantation

The world’s first partial facial transplant was performed in 2005 on a 38-year-old female whose face was severely injured by a dog bite.³⁰ Today, facial transplantation (facial CTA) has evolved into a technique that brings together principles from microsurgical reconstruction with those of human organ transplantation. Although it is now a viable option for those with extensive tissue defects, several factors need to be considered to optimise patient outcome.

Pre-operative considerations

The donor allograft needs to be matched to the recipient to minimise the risk of post-operative rejection. While in solid organ transplantation blood group matching helps prevent anti-A or anti-B activation and thereby hyperacute rejection, in facial transplantation antibody modulation/removal is thought to overcomplicate the transplant process without sufficient evidence for its implementation.³⁰

Similarly, though in solid organ transplantation human leukocyte antigen (HLA) matching provides insight into the relative risk of rejection, in facial CTA the allograft is histologically heterogenous and HLA matching has not been shown to have a significant impact on survival.³¹ On the other hand, prefacial transplant crossmatch assays are recommended. Crossmatching uses donor lymphocytes and recipient sera to determine whether a potential recipient has circulating antibodies against mismatched donor HLA antigens.³² This is an important pre-operative step in facial CTA since it helps reduce the risk of serious facial allograft rejection and can be performed within the time-frame of facial graft harvesting. Additional serological screening includes donor and recipient screening for infectious diseases, typically assessing for HIV, hepatitis, human T-cell lymphotropic virus, cytomegalovirus, syphilis and Epstein Barr virus.^33,34

As well as matching the donor allograft to the recipient on an immunological basis it is important to consider that the optimal facial transplantation also has a good aesthetic result. For this to be achieved, the donor skin tone should be as close as possible to that of the recipient. In most cases the donor allograft tone is assessed and matched using digital photography.³⁵

Pre-operative planning also includes vascular evaluation of the face, typically by colour Doppler sonography. This is particularly important since panfacial injuries may also include significant arterial deficits.³⁶ Furthermore, the branching pattern of the facial artery has been reported to vary between individuals and, in a small minority of individuals, the main trunk has been found to be absent or rudimentary. ³⁷ Colour Doppler sonography can be used to establish an alternative vessel in the event of facial artery absence.

Surgical considerations

Despite the complexity of facial transplantation, to date transplant loss as a result of surgical failure has not been reported. This is partly attributable to the high skill level of the surgeons performing the procedures. However, another important factor is the good circulation in the head and neck. Successful transplantation requires careful considerations both while harvesting and during transplantation.³⁸

Cold ischaemia time is an important determinant of success in solid organ transplantation. To minimise tissue damage secondary to prolonged cold ischaemia time, facial allografts are harvested from brain-dead, heart-beating donors with most of the facial dissection performed with circulatory maintenance, leaving only the final surgical steps to be completed after cross clamp time.³⁹ Some surgical teams perfuse and store the allograft in organ preservation solution to minimise tissue damage and blood congestion during cold ischaemia time.³⁸

The extent of the surgical procedure required with facial allografts depends on the composition of the tissues being transplanted. Most procedures have included transplantation of the eyelids, nose, cheeks and lips. Approximately half of reported cases also included bone transplantation, generally of the mandible and/or maxilla and requiring open fixation.38 While the whole face and maxilla can be revascularised by connecting a single facial artery,⁴⁰ most surgeons performing facial transplantations carry out bilateral facial or external carotid anastomosis using end-to-end microsurgical techniques.⁴¹

Venous drainage is achieved with bilateral anastomosis of the external jugular vein, facial vein or the thyrolinguofacial trunks. Motor function is achieved using neurorrhaphy of the facial nerve while sensation is provided using neurorrhaphies connected to the infraorbital nerve, mental nerve and, less commonly, the supraorbital nerve.⁴²

Immunological considerations

The most important complications following facial transplantation are those associated with immunosuppressive therapy. Immunotherapy strives to suppress allograft rejection while minimising toxic side effects.²⁹ Rejection may be hyperacute (within 48-hours of surgery), acute (days/months post-transplantation), or chronic. Though hyperacute allograft rejection has not been reported following facial CTA, the skin and oral mucosa are highly immunogenic and make up the majority of a composite facial allograft. Indeed, at least one episode of acute rejection has occurred in every facial CTA recipient.⁴³

Immunosuppression regimens following facial transplant mirror those used in solid organ transplantation – therapy consists of an “induction” phase immediately following transplantation, and continuous lifelong “maintenance” thereafter. Any rejection episodes are managed by “treatment” or “rescue” therapy in which the level of immunosuppressive therapy is increased.⁴⁴ Immunotherapies act by inhibiting the stimulation, proliferation and differentiation of lymphocytes. Polyclonal anti-thymocyte globulins (ATG), anti-interleukin-2 (IL-2) receptor monoclonal antibodies, anti-CD3 monoclonal antibodies and the calcineurininhibitor Tacrolimus may be used for induction therapy while maintenance is typically achieved by a triple therapy of Tacrolimus, Mycophenolate mofetil and prednisolone.⁴⁵ All immunosuppressive agents are associated with toxic side effects and potential to cause serious complications (Table I).⁴³

Table I.

Facial CTA in austere and war zone environments - benefits, challenges and considerations

Craniomaxillofacial injury is a leading concern globally,⁴⁶ especially in austere environments where the risk of severe facial injury is higher, injury prevention measures are often nonexistent, trauma care and rehabilitation systems are usually poorly resourced, and there is little (if any) social welfare infrastructure. The large burden of trauma (estimated at approximately 90%) is borne by developing countries,⁴⁷ with a higher preponderance in areas of civil strife. In situations likely to cause injury, the face is particularly at risk of harm due to its exposure. The global incidence of craniomaxillofacial injury is rising,⁴⁸ a trend attributable to socioeconomic, environmental, cultural and legislative factors. In lowand middle-income countries road traffic accidents (RTAs) are the principal cause of maxillofacial injury^50-51 but in areas of socio-political unrest and armed conflict this is overtaken by assault and inter-personal violence. This is highlighted in retrospective studies covering war injuries in Lebanon,^52-54 Iraq,^52,55,56 Afghanistan,^52,57 Somalia^52,58 and Vietnam.^52,58,59 Though injuries to the trunk reduced with the introduction of protective vests for military personnel, the high incidence of craniomaxillofacial injuries has continued, accounting for up to 40% of combat injuries.⁵²

The dramatic disfigurement following craniomaxillofacial trauma, with resulting loss of self-perception, identity, communication and recognition by others is life-altering for the patient. ⁶⁰ The problem is compounded by the fact that disfigurement often leads to the patient being ostracised by their community. Facial composite tissue allotransplantation (CTA) has the potential to provide the patient with optimal functional and cosmetic results in situations where alternative approaches are unable to replace the refined structure of the face, function of muscle that has been lost, and the interplay of sensation and movement. Nonetheless, facial transplantation presents particular challenges that may severely limit its feasibility in austere environments and thereby restrict its choice as a first-line option in these circumstances.

To date, forty-one partial and full facial CTA procedures have been reported worldwide.⁶¹ As the number of procedures performed increases, challenges associated with the practicality, risks, and costs associated with facial CTA are emerging and need to be addressed.

In preparing to introduce facial CTA in lowincome countries, the first challenge is that of acceptance and inclusion of the procedure within the health law of the country in which it is to be performed in.⁶² Once the health ministry has agreed to issue the required surgical license, subsequent barriers relate to finance. Unlike in the UK (NHS funded) or the US (primarily funded by the Department of Defence),³⁹ transplant programmes in low-income countries are often funded on a tripartite basis: by the patient, social security institutions and the health ministry.⁶² Further financial barriers include maintaining the multidisciplinary team required to perform the procedure. Successful outcome of facial CTA requires the combined work of plastic surgeons, transplant surgeons, anaesthesiologists, psychiatrists and social workers. The surgery is not performed on a routine basis, and so in situations where resources are scarce it may not be feasible to sustain the assembly and sufficient training of this multidisciplinary team within a hospital.

Though performing facial CTA involves a hefty initial financial outlay, analyses comparing the cost of this procedure with that of conventional reconstruction reveal similar cost profiles when adjustments based on severity of deformity and area of tissue coverage have been made,⁶³ with increasing cost benefit over time.⁶⁴ Given that one would expect costs for facial CTA to reduce with increasing surgical experience it is possible that, in the longer term, facial CTA may prove to be equally (if not more) cost-effective as conventional reconstructive techniques. Further analysis is needed to confirm this. The applicability of these cost profiles with specific reference to austere environments also needs to be assessed. It is however reasonable to propose that facial CTA has the potential to become a more cost-effective (as well as a surgically optimal) option further in the future.

Many of the challenges associated with facial CTA mirror those of solid organ transplantation. A major obstacle for both in low-income countries is a lack of available cadavers - low-income countries are associated with the lowest cadaver organ donation rates.⁶⁵ This is attributable to a combination of factors including insufficient hospital infrastructure (e.g. absence of a trauma unit), poor knowledge about organ donation and difficulty obtaining familial consent.⁶⁶ Donor selection and acceptance by the donors’ families is a particular challenge in the case of facial CTA since the procedure does not involve vital organs. The availability of suitable donors is further limited by the higher prevalence of severe infectious disease such as HIV and hepatitis. Data from high-income countries suggests that new systems of donation (e.g. using an organ donor registry) may increase cadaver organ donations through increased public awareness.⁶⁷ However, the benefit of this in low-income countries, particularly with regards to facial CTA donors, remains unclear.⁶⁸

Additional risks associated with the surgical procedure and post-operative care need to be addressed also. The major complication associated with facial CTA is that of allograft rejection. Though immuno-suppressive therapy is able to deal effectively with acute rejection, chronic rejection for both solid organ transplant and facial CTA will be an important future concern. Facial transplants are at risk of failure even ten to twenty years following surgery since vasculopathy (intimal proliferation and arterial occlusion) will inevitably evolve over time.⁶⁹ Continuous monitoring of the skin and arteries along with early use of mammalian target of rapamycin (mTOR) inhibitors or human immunoglobulin (as following heart transplantation) may reduce this risk. The longest recorded follow-up is ten years but this is likely to be significantly lower and more problematic in developing countries.⁷⁰ Table II summarises the facial CTA cases published to date, highlighting the complications associated with the procedure.^{30,40,42,60,71-89}

Post-CTA complications most commonly relate to infection. This is of particular importance in developing countries and areas of conflict. Limited personal hygiene often makes establishing aseptic wound dressings in the ward difficult.⁹⁰ Furthermore, the majority of patients in these circumstances are malnourished, which increases the risk of intra-operative complications and prolongs wound healing, both factors contributing to increased risk of infection. The requirement for immunosuppressive therapy to prevent allograft rejection heightens the chance of opportunistic infection further. Pre-operative prophylaxis and post-operative use of anti-infection agents may reduce the incidence and/or severity of infection.⁹¹ Further concern centres around the possible adverse effects from long-term use of the various medications that are required post-operatively. The balance between need for immunosuppressive therapy, anti-infectious agents and the possible ensuing nephrotoxicity, hepatotoxicity and other adverse effects needs to be carefully considered and monitored, which will necessitate regular follow-up appointments.⁹¹

There is no doubt that performing facial CTA in austere settings presents particular problems and alternative reconstructive methods should be actively considered. Conventional autotransplantation techniques have had successful outcomes in resource-limited situations^70,92 but these too carry their own risks. Deciding the most appropriate approach to facial reconstruction thus poses a dilemma – should one opt for conventional reconstructive techniques, or undertake riskier but potentially superior reconstruction by allotransplantation? An additional consideration is that allotransplant failure would lead to further surgery and even less favourable results than if autologous reconstruction had been used in the initial surgery. Therefore, the decision to opt for facial allotransplantation should be made early in the reconstructive care pathway, in full discussion with the patient, and with due consideration for available resources. This is even more pertinent in austere and/or war-zone settings where risks are higher and the need for additional surgery in an over-stretched hospital service is to be avoided as much as possible.

Table II.

Conclusion

Facial allotransplantation is recognised as a procedure with potentially huge functional, psychological and social benefits for individuals with severe, life-changing facial defects. Success depends on meticulous attention to pre-, intra- and postoperative care. This involves investment of a large amount of resources for each individual case and, in austere settings, it may be difficult to justify allocating sparse resources for such a procedure. However, given the huge benefit that is achievable in such patients, a case can still be made in these circumstances, provided there is careful patient selection and adequately trained surgeons.