Vascularized Composite Tissue Allotransplantation

T. Nicole Kelley, MS, ACNP, CCRN, CPSN, CANS, RNFA

Linda A. Evans, RN, PhD

I. INTRODUCTION

“Organ transplant” generally presumes the implantation of a kidney, heart, or other solid internal organ. In recent times, the concept of transplanting combination tissue grafts, which may include bone, skin, muscle, tendon, and nerve, has evolved.¹^,² Composite transplantations have been performed to replace body parts lost to disease,³ trauma,⁴^,⁵^,⁶^,⁷ or congenital malformations.⁸

This chapter provides information for nurses caring for patients undergoing vascularized composite tissue allotransplantation (VCA), including historical perspectives, ethical considerations, government and agency oversight, patient evaluation criteria and preparation for surgery, novel surgical interventions, specialized considerations for perioperative care, VCA benefits and risks, and long-term patient monitoring care related to graft monitoring and immunosuppression. Specific focus is on facial and hand transplantation.

II. OVERVIEW

A. Composite tissue allotransplantation (CTA)

Definition: transplantation of histologically different tissues including skin, connective tissue, blood vessels, muscle, ligaments, cartilage, tendon, bone, nerve tissue, and tissue-based products.⁹^,¹⁰
CTA: early nomenclature for graft tissue regarding facial and hand transplants.¹¹
Viewed as a complex science during the conceptual phase with multiple clinical, ethical, and psychosocial considerations¹²:
- Determination of patient selection criteria
- Societal considerations
- Refining procurement techniques
- Limitations of obtaining a fully informed consent
- Immunological response and immunosuppressant requirements
- Ethical issues
- Donor family considerations
An estimated 7 million people per year in the United States could benefit from CTA.²^,⁸^,¹¹

B. Vascularized composite allotransplantation (VCA)

Definition: the simultaneous transplantation of multiple tissue types such as muscle, bone, nerve, and skin as a functional single unit (e.g., hand or face).⁹^,¹³^,¹⁴
Goal: restoration of sensory and motor functional status, anatomy, appearance, and psychosocial well-being including self-esteem and reintegration into family and social life.¹⁵^,¹⁶^,¹⁷^,¹⁸
Surgical option when soft tissue and bone loss is accompanied by severe cosmetic, sensory, and functional deficiencies due to disease,³ trauma,⁴^,⁵^,⁶^,¹⁹ or congenital malformations.⁸
VCA procedures are considered only after all conventional reconstructive methods, or prosthetics in the case of hand amputations, have failed.⁸^,¹⁴
To date, more than 150 VCAs have been reported and include hand, abdominal wall, tongue, trachea, larynx, face,²^,²⁰^,²¹^,²²^,²³ esophagus, and a vascularized knee and femurs.²^,²⁴
No cases of pediatric facial transplantation have been reported to date.²⁴
Current clinical trials:
- Facial allotransplantation: five trials actively recruiting¹³
- Hand allotransplantation: five trials actively recruiting¹⁴
Criteria for body parts defined as a VCA per the Department of Health and Human Services (DHHS).⁴^,²⁵^,²⁶
- Recovered from a human donor as an anatomical structural unit and contains multiple tissues.
- Transplanted into a human recipient as an anatomical structural unit.
- Vascularized tissue requiring blood flow by surgical connection of vessels to function following transplantation.
- Processing does not alter the original characteristics of the “organ graft.”
- The donated graft performs the same basic functions in the recipient as in the donor.
- Not combined with another article or device.
- Susceptible to ischemia requiring rapid re-establishment of blood flow; thus can be stored only temporarily (cold storage with preservation medium with the intention of implantation within hours of recovery).
- Susceptible to allograft rejection requiring donor-recipient matching and generally requiring immunosuppression.
Short-term results of VCA transplantation have been positive.¹²^,²⁷
Long-term physical, emotional, and psychological effects on both VCA hand and face recipients as well as long-term (>10 years) consequences to the donor’s family are unknown.²⁷
Emotional and ethical impact on health care team members involved in facial transplant surgery and patient care has been positive.²⁸^,²⁹

III. HISTORICAL PERSPECTIVE

A. Timeline: The development of VCA⁴^,¹⁰^,¹²^,²²^,²³^,²⁴^,²⁹^,³⁰^,³¹^,³² (Table 16-1).

B. Approximately 35 facial transplant procedures have been reported.³¹^,³²^,³³^,³⁴^,³⁵^,³⁶

C. Facial transplant procedures 1st to 29th: 2005 to 2014³¹^,³² (Table 16-2).

TABLE 16-1 Timeline—Development of Vascular Composite Allograft Transplantation

Date	Event
348 AD	Legendary account of the transplantation of leg by Cosmos and Damian¹²
Late 16th century	Transplantation of a nose by Gaspare Tagliacozzi¹²
Early 20th century	Canine limb transplant by Carrel¹²
Early 20th century	Heterotopic allotransplantation of the heads of dogs by Guthrie¹²
1956	First successful human kidney transplant. Donor and recipient were identical twins mitigating risk of rejection.¹²
1963	Ecuador: first human hand transplant. Experienced acute rejection. Removed 3 wk after transplant²⁹
1988	First successful laryngotracheal transplant²⁴
1990s	Series of knee and femur transplantations with “long-term survival elusive”²³
1994	Replantation of full facial tissue (autotransplant) in India¹²
1998	Second ever human unilateral hand transplant performed in France. First to survive more than 2 y. Eventually rejected and removed because of noncompliance¹⁰
1999-2013	>90 hand transplants in 46 patients. No mortality reported. Multiple episodes of rejection successfully reversed with medication management³⁰
2000	World’s first bilateral upper extremity transplant²³
2005	First human facial transplantation in France⁴
2009	U.S. Department of Defense acknowledges facial transplant as a research priority in effort to care for wounded soldiers.¹²
2005-2014	>30 facial allotransplantation procedures have been reported as of May 2015.^22,31,32,33

D. Five facial transplant deaths have been reported to date.³¹^,³³^,³⁴^,³⁵^,³⁶

First patient was noncompliant with immunosuppressive treatment.
Second patient developed recurrent squamous cell carcinoma of the hypopharynx.
Third patient developed multidrug-resistant Pseudomonas aeruginosa infection, graft failure, and cardiac arrest after a combined face and double-hand transplant.
The fourth and fifth deaths were related to tumor recurrence and self-inflicted injury.

IV. ETHICAL CONSIDERATIONS

A. Innovative nature of VCA procedures lends themselves to increased scrutiny.²⁸

B. Arguments in support of²⁰^,³⁶^,³⁷ and against²⁰^,³⁷^,³⁸^,³⁹ VCA were abundant during conceptual phase.

C. Concern that the innovative nature of the procedure precluded a fully informed consent.²⁸

D. Most frequently discussed ethical issue during early discussions was concerned that the need for lifelong immunosuppressive therapy following transplantation did not warrant the cost or consequences of potential infections, malignancies, renal failure, diabetes, and death.²⁹

TABLE 16-2 Facial Transplant Procedures: 2005-2014

	Date	Age/Gender	Location	Lead Surgeon	Mechanism of Injury
1	November 2005	38/female	Amiens, France	Devauchelle and Dubenard	Dog bite
2	April 2006	30/male	Xi’an, China	Guo	Bear attack
3	January 2007	29/male	Creteil, France	Lantieri	Neurofibromatosis
4	December 2008	46/female	Cleveland, OH, USA	Siemionow	Ballistic trauma
5	March 2009	27/male	Paris, France	Lantieri	Shooting accident
6	April 2009	30/male	Paris, France	Lantieri	Burn
7	April 2009	60/male	Boston, MA, USA	Pomahac	Electrical burn/traumatic injury
8	August 2009	33/male	Paris, France	Lantieri	Ballistic trauma
9	August 2009	42/male	Valencia, Spain	Cavadas	Cancer/radiation for tumor injury
10	November 2009	27/male	Amiens, France	Devauchelle and Dubenard	Ballistic trauma
11	January 2010	34/male	Seville, Spain	Gomez-Cia	Neurofibromatosis
12	March 2010	30/male	Barcelona, Spain	Barrett	Ballistic trauma/shooting victim
13	June 2010	35/male	Paris, France	Lantieri	Neurofibromatosis
14	March 2011	25/male	Boston, MA, USA	Pomahac	Electrical burn/traumatic injury
15	April 2011	30/male	Paris, France	Lantieri	Ballistic trauma
16	April 2011	41/male	Paris, France	Lantieri	Ballistic trauma
17	April 2011	30/male	Boston, MA, USA	Pomahac	Electrical burn
18	May 2011	57/female	Boston, MA, USA	Pomahac	Animal attack (chimpanzee)
19	January 2012	Unknown/male	Ghent, Belgium	Blondeel	Industrial accident
20	January 2012	45/male	Antalya, Turkey	Ozkan	Burn
21	February 2012	25/male	Ankara, Turkey	Nasir	Burn
22	March 2012	20/female	Antalya, Turkey	Ozkan	Ballistic trauma
23	March 2012	37/male	Baltimore, MD, USA	Rodriguez	Ballistic trauma, gunshot wound
24	May 2012	34/male	Antalya, Turkey	Ozkan	Burn
25	September 2012	Female	Amiens, France	Devauchelle and Dubenard	Vascular tumor
26	February 2013	44/female	Boston, MA, USA	Pomahac	Chemical burn
27	May 2013	33/male	Gliwice, Poland	Maciejewski	Blunt trauma
28	July 2013	27/male	Antalya, Turkey	Ozkan	Ballistic trauma
29	September 2014	Middle age/male	Ohio, USA	Papay	Motor vehicle crash
From Khalifian S, Brazio PS, Mohan R, et al. Facial transplantation: the first 9 years. Lancet. 2014;384(9960):2153-2163. Available at http://dx.doi.org/10.1016/S0140-6736(13)62632-X,www.TheLancet.com; Cleveland Clinic. Face Transplant: Rebuilding Lives. Available at http://www.clevelandclinic.org/lp/face/index.html?utm_campaign=facetransplant-url&utm_medium=offline&utm_source=redirect. Accessed January 15, 2015; Rodriguez E. State of the art: facial reconstruction and transplantation. International Conference sponsored by AO North America, May 15-17, 2015, New York, NY. Available at www.facerecon2015.org.

E. Financial burden is considerable, including lifelong immunosuppression.²⁰^,²⁹^,³⁶^,³⁷

F. Level of disfigurement appropriate for transplant potentially has subjective quality.²⁸

G. Unlike solid organ transplant, VCA grafts likely require immunosuppression in the treatment of non-life-threatening conditions versus life-threatening conditions of the solid organ transplant patient.⁹

H. Hand and facial transplantation is considered “life changing and/or life giving” not “lifesaving” and thus has been criticized for exposing otherwise healthy people to the risks of lifelong immunosuppression.³⁰^,³¹

I. Lifelong immunosuppressive therapy is known to increase the development of general metabolic derangements such as renal insufficiency and failure, hypertension, hyperglycemia, systemic infections, opportunistic infections, and malignancies.²⁹

J. Complete facial graft loss, depending on the extensiveness of the donated tissue, could result in severe disfigurement, dysfunction, morbidity, and/or death.¹⁰^,²³^,²⁹^,⁴⁰

K. The “life-giving” nature of VCA procedures, by virtue of “normalizing” the patient’s appearance, has been lauded as an ethical mandate for these procedures by proponents.¹²^,⁴¹

L. Due to the innovative nature of these procedures and potential clinical and ethical concerns, full institutional review board (IRB) currently guides efforts.²⁸

V. PSYCHOSOCIAL CONSIDERATIONS

A. Understanding the “role of face” in social interactions.²⁰

B. Interpreting how facial expression affects an individual’s personal identity and societal roles.⁴¹^,⁴²

C. Quantifying the impact of an individual’s facial disfigurement or loss of hands on their self-esteem, mood, independence, and social reintegration.²⁰

D. Evaluating a patient’s expectations regarding the outcome of facial and/or hand transplant surgery.⁴²

E. Assessing the availability of appropriate social supports for the transplant recipient postoperatively.³^,²⁰

F. Assessing the patient’s potential for adherence to the therapeutic regimen.

G. Procedures are only performed at select institutions, thus making the geographical considerations for follow-up care significant if the recipient is unable to easily access the VCA center.¹²

VI. U.S. FEDERAL GOVERNMENT OVERSIGHT VIA HEALTH RESOURCES AND SERVICES ADMINISTRATION (HRSA) FINAL RULE AND INSTITUTIONAL PREPAREDNESS²⁶

A. VCAs were originally under the auspices of the Food and Drug Administration, which regulates human cells, tissues, and cellular tissue-based products.

B. VCAs were subsequently added to the definition of “organs” under the auspices of the Health Resources and Services Administration (HRSA), which oversees solid organ transplantation through the Organ Procurement and Transplantation Network (OPTN)—July 13, 2013.

Purchase or sale of VCAs prohibited.
Issues concerning allocation and recipient safety currently fall under the auspices of the OPTN.²⁶

C. Final Rule effective July 3, 2014; OPTN now responsible for establishing policies pertaining to the procurement, allocation, and transplantation of VCAs.

D. The United Network for Organ Sharing (UNOS) establishes rules for allocation of solid organs but does not establish allocation regulations for potential VCA recipients.¹⁰

E. Facility criteria: VCA must be completed in an organized and synchronized health care delivery system; ideally, a center of excellence with experience in specializing in the treatment of complex craniofacial defects utilizing microsurgical techniques as well as medical science to manage vascularized composite transplants.²⁶^,⁴³

VCAs under a research protocol/IRB must have approval by IRB with consideration of posting to the National Institutes of Health Clinical Trials Web site (https://clinicaltrials.gov/).²⁶
Approval by the designated organ procurement organization, requiring hospitals to comply with the rules and requirements of the OPTN as a condition of participation in Medicare and Medicaid programs.²⁶
In order to perform VCAs, an institution must
- Be a designated organ-specific transplant center
- Become a member of the OPTN
- Comply with OPTN data submission requirements²⁶
Institutions failing to comply with OPTN policies are subject to sanctions and possible termination from Medicare and Medicaid programs.²⁶

VII. CLINICAL INDICATIONS AND REQUIREMENTS MEETING THE AMERICAN SOCIETY FOR TRANSPLANTATION CRITERIA FOR VCA TRANSPLANTATION⁹

A. Facial VCA

Facial Transplant Guiding Principles for Determining Medical Necessity⁹^,²⁵:
- Defects comprising 25% or more of the facial surface area and/or involving one or more central facial units such as the eyelids, lips, mouth, or nose.⁹^,²⁵
- Transplantation of underlying bone (maxilla/mandible/nose) or tongue is indicated.
- Defects are typically the result of trauma, burns, congenital conditions such as neurofibromatosis, or tumor resection resulting in severe irreversible aesthetic, sensory, and motor functions of the face.²⁹
- Important functions of the face such as air humidification, nonverbal expression, intelligible speech, breathing, oral competence (ability to chew, swallow, kiss, and control drooling), facial sensation, and eyelid closure are absent.⁹^,⁴³^,⁴⁴^,⁴⁵
- Conventional reconstructive options have failed restoration and are deemed unsatisfactory.⁹^,⁴³^,⁴⁴^,⁴⁵
- Severe anatomical and functional abnormalities have resulted in detrimental effects on the patient’s psyche, perception of body image, quality of life, and social interactions with loss of integration with family, friends, colleagues, and depression.²⁵
American Society for Reconstructive Transplantation (ASRT) Advisory Council medically necessary Clinical Criteria⁹^,²⁵:
- Comprehensive medical history and physical examinations conducted by a plastic and reconstructive surgeon, and/or a craniofacial surgeon, to evaluate the need for transplantation.
- Surgical treatment plan (which outlines the surgical approach and the prognosis for improvement of clinical signs/symptoms pertinent to the diagnosis) has been developed.
- Comprehensive medical history and physical examinations have been conducted by a transplant physician or surgeon to evaluate the physical ability of the patient to undergo transplantation.
- Comprehensive psychosocial and mental health examinations have been performed to evaluate the patient’s motivation and ability to successfully manage a VCA allograft.
- The patient has had inadequate or failed functional recovery with conventional reconstructive surgical treatment and/or nonsurgical rehabilitation.
- The facial defect is accompanied by medical or functional complications and demonstrable loss of quality of life as determined by psychological evaluation.
ASRT Advisory Council Required Documentation of medical necessity including⁹^,²⁵
- Primary and secondary diagnoses with clinical symptoms and comorbid conditions
- Complete history and physical, prior failed treatments and surgeries
- Photographic and radiologic studies confirming the facial defects and the planned surgical treatment

B. Hand VCA

Hand Transplant Guiding Principles for Determining Medical Necessity⁹^,²⁵
- Amputation or irreversible traumatic functional loss.
- Failed use of prosthetic devices unless such devices were deemed medically contraindicated.
- Patients with congenital deficits should seek opportunities in other clinical trials until research demonstrates plasticity of neural networks.
Eligibility determination is based on a combination of clinical data and indicators affecting the risks and benefits of the transplantation.
ASRT Advisory Council medically necessary Clinical Criteria⁹^,²⁵:
- Comprehensive medical history and physical examination conducted by a transplant physician or surgeon to evaluate the need for transplantation.
- Surgical treatment outlining the approach and prognosis for improvement of clinical findings pertinent to the diagnosis developed.
- Comprehensive medical history and physical examination conducted by a transplant physician or surgeon evaluating the health status of the patient to undergo transplantation.
- Comprehensive psychosocial and mental health examinations have been performed to evaluate the patient’s motivation and ability to successfully manage a VCA allograft.
- Patient is generally over 18 years of age and has had inadequate functional recovery with previous conventional reconstructive surgical interventions and/or nonsurgical rehabilitation.
- The amputation or loss of function is accompanied by
  - Medical or functional complications
  - Demonstrable loss of quality of life as determined by psychological evaluation
  - Tissue necrosis or ulcerations unresponsive to nonsurgical treatments
- Comorbid etiologies have been considered and ruled out.

VIII. EVALUATION/SCREENING OF POTENTIAL VCA CANDIDATES AND INFORMED CONSENT REQUIREMENTS¹⁶^,¹⁷^,¹⁸^,²³^,²⁵^,²⁷^,⁴²^,⁴⁶^,⁴⁷

A. “General” eligibility under current research protocols in the United States

Currently, upper extremity and facial VCA procedures are considered “research protocols.”³¹^,³⁵^,⁴⁸^,⁴⁹
Inclusion and exclusion criteria vary between individual institutions including age limitations, infectious disease states, and US citizenship to name a few.¹⁵^,⁴⁵^,⁴⁶^,⁵⁰^,⁵¹^,⁵²
Inclusion criteria
- Face VCA
  - Facial defect or injury requiring facial transplantation as determined by the treating plastic and reconstructive surgeon.
  - Autologous tissue options must be available in the event of facial graft failure.
- Upper extremity/hand VCA²³^,⁴⁶^,⁴⁷^,⁵¹^,⁵²
  - Recent (<6 months) or remote unilateral or bilateral upper limb loss below the shoulder desiring limb transplantation.
  - Unilateral arm transplant may be considered at some institutions even if the transplanted arm is the nondominant arm.²³
  - Single dominant hand or multiple-limb amputation.⁴⁶^,⁵⁰
  - Patient consent to bone marrow transfusion as part of treatment regimen is institution specific.⁴⁶^,⁵²
  - Blind amputees may be considered poor candidates as sensory return in the hand may not provide sufficient protection; conversely, benefits to blind patients may outweigh this risk (K. Knott, personal communication, October 2nd, 2014. Johns Hopkins University, Transplant Nurse Practitioner).
  - Failed prosthetic trials.⁴⁶^,⁴⁷^,⁴⁹^,⁵¹
  - Upper extremity/hand transplant: clinical trials dictate that the patient must be cancer-free for 5 to 10 years.⁴⁶^,⁴⁷^,⁴⁹^,⁵⁰^,⁵¹
Exclusion criteria: face, upper extremity, and hand VCA¹⁵^,¹⁶^,¹⁷^,¹⁸^,²⁵^,³⁵^,⁴⁷^,⁴⁹^,⁵⁰^,⁵¹
- Preexisting diseases or medical conditions that would negatively impact success.
  - Expose the patient to unacceptable risks under immunosuppressive treatments.
  - Unacceptable surgical risk to the recipient from transplantation.
  - Absolute and relative contraindications are determined by the specific institutional selection committees: diseases may include inherited coagulopathies, connective tissue or collagen diseases, amyloidosis, etc.
- Human immunodeficiency virus (HIV) positive (active or seropositive) (relative contraindication).
- Hepatitis B or C virus positive (relative contraindication).
- Active infection including, but not limited to, tuberculosis, toxoplasmosis, or viral encephalitis.
- Current malignancy.
- Malignancy history within the last 5 years⁴⁶^,⁴⁷^,⁴⁹^,⁵⁰ to 10 years.¹⁶^,⁵¹
  
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