Chẩn Đoán Và Điều Trị Phẫu Thuật Tái Tạo Hiện Đại (CURRENT Reconstructive Surgery)

ALLOPLASTIC CRANIOFACIAL IMPLANTS • 33
Malar. Patients who seek malar augmentation may have
midface hypoplasia or normal anatomy and usually seek
greater prominence of their middle malar prominence. 38
Paranasal. A relative defi ciency in lower midface projec-
tion may be congenital or may be acquired, particularly
after cleft surgery and trauma. Patients with satisfactory
occlusion and midface concavity can have their aesthetic
desires satisfi ed with skeletal augmentation. Implantation
of alloplastic material in the paranasal area can simulate
the visual effect of LeFort I advancement. 39
Infraorbital Rim. Augmentation of this area is useful
for patients with severe defi ciencies of the midface and
infraorbital rim area that result in excessively prominent
eyes. Infraorbital rim augmentation can effectively reverse
the “negative” vector of midface hypoplasia. 40
Most often, infraorbital rim augmentation is combined
with a subperiosteal midface lift which elevates the mid-
face soft tissues on its new infrastructure ( Figure 3-12 ).
Chin. The projection of the chin should be inter-
preted in the context of the surrounding facial features,
A
B
C
FIGURE 3-12. A 30-year-old woman with Graves disease underwent medial and
lateral orbital decompression with preservation of the lateral orbital rim. Globe-rim
relations were further improved by augmenting the infraorbital rim, elevating the midface
soft tissue and performing lateral canthopexy. (A) Preoperative and postoperative frontal.
(B) Preoperative and postoperative lateral. (C) Diagrammatic representation of procedure.

34 • CHAPTER 3
FIGURE 3-13. A 30-year-old with mandibular defi ciency and orthodontically
corrected occlusion underwent chin and mandibular augmentation with alloplastic
implants. (A) Pre- and postoperative frontal. (B) Pre- and postoperative lateral.
(C) Artist’s rendition of surgery.
A
B
C

ALLOPLASTIC CRANIOFACIAL IMPLANTS • 35
including the projection of the nose, the relationship to
the lips, and the depth of the labiomental sulcus. There
is a consensus among surgeons that the ideal profi le por-
trays a convex face with the upper lip projecting inci-
sions approximately 2 mm beyond the lower lip and the
lower lip projecting approximately 2 mm beyond the
chin. 41
Early implant designs augmented the mentum only
and often created a stuck-on appearance, as a result of
failure of the lateral aspect of the implant to merge with
the anterior aspect of the mandibular body. “Extended”
chin implants have tapered lateral extensions that enable
the chin implant to better merge with more lateral man-
dibular contours. 42 , 43 I prefer a two-piece chin implant. 44
A two-piece implant allows the inferior border of the
implant to follow the inferior border of the mandi-
ble. This is usually not possible with a one-piece chin
implant.
Ramus and Body
Patients with skeletal mandibular defi ciency who have
had their malocclusion treated with orthodontics alone
are left with mandibular skeletal defi ciencies that may be
displeasing. The skeletal anatomy associated with man-
dibular defi ciency that can be camoufl aged with implants
include the obtuse mandibular angle with steep mandib-
ular plane and decreased vertical and transverse ramus
dimensions ( Figure 3-13 ). The addition of an extended
chin implant will camoufl age the poorly projecting
chin. 45
Many patients perceive a wider lower face with a
well-defi ned mandibular border as an enhancement to
their appearance. Patients in this treatment group often
present with a desire to emulate the appearance of mod-
els, actors, and actresses who have a defi ned, angular
lower face. This patient group benefi ts from implants
designed to augment the ramus and posterior body of
the mandible.
Implants Used to Camoufl age
Soft Tissue Depressions
The implants discussed in this section are designed to
increase the surface projection of the facial skeleton. Some
surgeons have used implants placed on the facial skeleton
to disguise overlying soft tissue volume inadequacy, usually
caused by involutional changes brought on by age. These
include the submalar, prejowl, and tear trough implants.
Augmentation of the skeleton to compensate for a soft tis-
sue defi ciency should be extremely conservative. Skeletal
augmentation does not give the same visual effect as the
soft tissue augmentation. Similarly, soft tissue augmenta-
tion beyond 1 or 2 mm provides a different visual effect
than skeletal enlargement. For example, a chin point aug-
mented with fat to increase projection by 5 mm reads as a
fatty chin pad, not as a more projecting chin.
Complications. There is no scientifi c data to document the
complication rate related to facial skeletal augmentation.
Prospective studies that control for surgical technique,
implant site, patient selection, and follow-up time do not
exist. Because all the biomaterials commonly used for facial
skeletal augmentation are biocompatible, complications are
usually technique related—improper implant size, contour,
or placement. Infections are unusual when implants are
placed through cutaneous incisions. When infection occurs,
the most reliable treatment is implant removal.
SUMMARY
Augmentation or replacement of nonload-bearing por-
tions of the facial skeleton with alloplastic materials
provides powerful means to restore or improve facial
appearance. Virtually any area of the facial skeleton can
be reconstructed. Requisites for success include implants
of appropriate size and shape, adequate soft tissue cover,
and careful subperiosteal dissection during exposure and
implant placement.
REFERENCES
1. Rubin JP, Yaremchuk MJ. Complications and toxicities of
implantable biomaterials used in facial reconstructive and
aesthetic surgery: A comprehensive review of the literature.
Plast Reconstr Surg . 1997;100:1336.
2. Klawitter JJ, Bagwell JG, Weinstein AM, Sauer BW. An evalu-
ation of bone growth into porous high density polyethylene.
J Biomed Mater Res . 1976;10:311.
3. Spector M, Flemming WW, Sauer BW. Early tissue infi ltrates
in porous polyethylene implants into bone: A scanning elec-
tron microscope study. J Biomed Mater Res . 1975;9:537.
4. Spector M, Harmon SL, Kreutuer A. Characteristics of tissue
ingrowth into Proplast and porous polyethylene implants in
bone . J Biomed Mater Res . 1979;13:677.
5. Berghaus A, Mulch G, Handrock M. Porous polyethylene
and Proplast: Their behavior in a bony bed. Arch Otorhino-
laryngol. 1984;240:1165.
6. Maas CS, Merwin GE, Wilson J, et al. Comparison of bio-
materials for facial bone augmentation. Arch Otolaryngol of
Head Neck Surg . 1990;116:551.
7. Eppley BL. Alloplastic implantation. Plast Reconstr Surg .
1999;104:1761.
8. Eppley BL, Sadove AM, German RZ. Evaluation of HTR
polymer as a craniomaxillofacial graft material. Plast Recon-
str Surg. 1990;86:1085.
9. Chiroff R, White E, Weber J. Tissue ingrowth of Replamine-
form implants. J Biomed Mater Res. 1975;6:29.
10. Gosain AK, Song L, Riordan P, et al. Part I: a 1-year study of
osteoinduction in hydroxyapatite-derived biomaterials in an
adult sheep model. Plast Reconstr Surg. 2002;109:619.
11. Gosain AK. Biomaterials for reconstruction of the cranial
vault. Plast Reconstr Surg. 2005;116:663.

36 • CHAPTER 3
12. Holmes R, Halger H. Porous hydroxyapatite as a bone graft
substitute in cranial reconstruction: A histometric study.
Plast Reconstr Surg . 1988;81:662.
13. Fiala TGS, Paige KT, Davis TL, et al. Comparison of artifact
from craniomaxillofacial internal fi xation devices: Magnetic
resonance imaging. Plast Reconstr Surg . 1994;93:725.
14. Saxe AW, Doppman JL, Brennan MF. Use of titanium surgi-
cal clips to avoid artifacts seen on computed tomography.
Arch Surg . 1982;117:978.
15. Fiala TGS, Novelline RA, Yaremchuk MJ. Comparison of CT
imaging artifacts from craniomaxillofacial internal fi xation
devices. Plast Reconstr Surg. 1993;92:1227.
16. Wehmoller MW, Eufi nge H, Kruse D, Massberg W. CAD
by processing of computed tomography data and CAM of
individually designed prostheses . Int J Oral Maxillofac Surg.
1995;24:90.
17. Eufi nger H, Wehmoller MW, Machtens E, et al. Reconstruc-
tion of craniofacial bone defects with individual alloplas-
tic implants based on CAD/CAM manipulated CT data.
J Craniomaxillofac Surg. 1995;23:175.
18. Eppley BL, Kilgore M, Coleman JJ. Cranial reconstruction
with computer generated hard-tissue replacement patient-
matched implants: Indications surgical techniques and long-
term follow-up. Plast Reconstr Surg . 2002;109:864.
19. Ledezma CJ, Hoh BL, Carter BS, et al. Successful use of
custom stereolithographic-designed high-density porous
polyethylene cranioplasty implants to correct cranial defects
after neurosurgical procedures. Submitted to the Journal of
Neurosurgery .
20. Taub PJ, Rudkin GH, Clearihue WJ, Miller TA. Prefabricated
alloplastic implants for cranial defects. Plast Reconstr Surg.
2003;111:1232.
21. Manson PN, Crawley WA, Hoopes JE. Frontal cranioplasty:
risk factors and choice of cranial vault reconstructive mate-
rial. Plast Reconstr Surg. 1986;77:888.
22. Hammon WM, Kempe LG. Methyl methacrylate cranio-
plasty: 13 years experience with 417 patients. Acta Neuro-
chir. 1971;25:69.
23. Rish BL, Dillon JD, Meirowsky AM, et al. Cranioplasty: a
review of 1030 cases of penetrating head injury. Neurosurgery.
1979;4:381.
24. Stelnicki EJ, Ousterhout DK. Prevention of thermal tissue
injury induced by the application of polymethylmethacry-
late to the calvarium. J Craniofac Surg. 1996;7:192.
25. Constantino PD, Friedman CD, Jones K, et al. Experimen-
tal hydroxyapatite cement cranioplasty. Plast Reconstr Surg .
1992;90:174.
26. Burstein FD, Cohen SR, Hudgins R, et al. The use of
hydroxyapatite cement in secondary craniofacial reconstruc-
tion. Plast Reconstr Surg. 1999;104:1270.
27. Constantino PD, Friedman CD, Jones K, et al. Hydroxyapa-
tite cement: I Basic chemistry and histologic properties. Arch
Otolaryngol Head Neck Surg . 1991;117:379.
28. Friedman CD, Costantino PD, Jones K, et al. Hydroxyapatite
cement. II. Obliteration and reconstruction of the cat frontal
sinus . Arch Otolaryngol Head Neck Surg. 1991;117:385.
29. Moreira-Gonzalez A, Zins J. The use of hydroxyapatite bone
cement in the repair of large full thickness cranial defects: a
caution. Presented at: American Association of Plastic Sur-
geons, 84th Annual Meeting; Scottsdale, AZ; 2005.
30. Matic D, Phillips JH. A contraindication for the use of
hydroxyapatite cement in the pediatric population. Plast
Reconstr Surg. 2002;110:1.
31. Bite U, Jackson IT, Forbes GS, et al. Orbital measurements
in enophthalmos using three dimensional CT imaging. Plast
Reconstr Surg. 1985;75:502.
32. Manson PN, Clifford CM, Su CT, et al. Mechanisms of global
support and post-traumatic enophthalmos. I. The anatomy
of the ligament sling and its relation to intramuscular cone
orbital fat. Plast Reconstr Surg. 1985;77:193.
33. Manson PN, Grivas A, Rosenbaum A, et al. Studies on
enophthalmos. II. The measurement of orbital injuries and
their treatment by quantitative computed tomography. Plast
Reconstr Surg. 1985;77:201.
34. Tessier P. Inferior orbitotomy. A new approach to the orbital
fl oor. Clin Plast Surg. 1982;9:569.
35. Glassman RD, Manson PN, Vanderkolk CA, et al. Rigid fi xa-
tion of internal orbital fractures. Plast Reconstr Surg. 1990;
86:1103.
36. Rubin PAD, Shore JW, Yaremchuk MJ. Complex orbital frac-
ture repair using rigid fi xation of the internal orbital skel-
eton. Ophthalmology. 1992;99:553.
37. Yaremchuk MJ, Manson PN. Reconstruction of the inter-
nal orbit using rigid fi xation techniques. In: Yaremchuk MJ,
Gruss JS, Manson PN, eds. Rigid Fixation of the Craniomax-
illofacial Skeleton . Boston, MA: Butterworth-Heinemann;
1992.
38. Whitaker LA. Aesthetic augmentation of the malar midface
structures. Plast Reconstr Surg . 1987;80:337.
39. Yaremchuk MJ, Israeli D. Paranasal implants for correction
of midface concavity. Plast Reconstr Surg . 1998;102:51.
40. Yaremchuk MJ. Infraorbital rim augmentation. Plast Reconstr
Surg . 2001;107:1585.
41. McCarthy JG, Ruff JG. The chin. Clin Plast Surg . 1988;
15:125.
42. Flowers RS. Alloplastic augmentation of the anterior man-
dible. Clin Plast Surg . 1991;18:137.
43. Terino EO. Facial contouring with alloplastic implants. Facial
Plast Surg Clin North Am . 1999;7:55.
44. Yaremchuk MJ. Improving aesthetic outcomes after alloplas-
tic chin augmentation. Plast Reconst Surg. 2003;112:1422.
45. Yaremchuk MJ. Mandibular augmentation. Plast Reconstr
Surg . 2000;106:697.

c h a p t e r 4
Reconstructive
Transplantation: Evolution,
Experience, Emerging Insights
Vijay S. Gorantla, MD, PhD / W.P. Andrew Lee, MD / Joseph E. Losee, MD
INTRODUCTION
Reconstructive transplantation is among the newest of
transplant areas and combines the time-tested techniques
of reconstructive microsurgery with the immunologic
principles of transplant surgery. It involves the trans-
plantation of composite tissues, including skin, muscle,
mucosa, ligament, tendon, nerve, blood vessel, bone, joint
and cartilage, bone marrow, and lymph nodes. 1 The over-
all goal of reconstructive transplantation is to improve
the quality of the life of patients with signifi cant tissue
defects.
There is currently no national database or registry in
the civilian population regarding the millions of individu-
als each year who sustain trauma or tumor extirpation or
undergo complex reconstruction for other congenital or
acquired tissue defects or defi cits. It is reasonable to esti-
mate that management of these disfi guring, disabling, and
debilitating tissue injuries/losses costs the US health care
system tens of millions of dollars each year. For example,
current surgical procedures after major trauma are lim-
ited by available tissues for reconstruction, morbidity
from extensive surgery, prolonged rehabilitation, and costs
of multiple surgeries. For such complex injuries, recon-
structive transplantation of composite grafts can achieve
near-perfect restoration of tissue defects with improved
functional and aesthetic outcomes and avoidance of mul-
tiple surgeries.
Despite the obvious advantages offered by recon-
structive transplantation, one factor has hampered its
widespread application. This is the need for long-term
immunosuppressive therapy to maintain the allograft.
The risks posed by antirejection drugs are considered by
many to be justifi ed in lifesaving procedures such as solid
organ transplants in patients with terminal organ failure.
However, such risks are considered to be too high a price
to pay for life-enhancing (nonlifesaving) transplants such
as hand or face composite grafts.
Reconstructive transplantation has now been performed
successfully at more than a dozen centers worldwide 2 and
at seven centers in the United States. 3 During the past
decade, more than 100 reconstructive transplant proce-
dures have been performed around the world, including
70 hand and 18 facial transplants, with encouraging out-
comes. The growth has been slow, largely due to initial
skepticism of the immunological feasibility 4 and currently
for concern for the life-long risks of immunosuppression. 5
There have been a few deaths and graft failures second-
ary to complications, noncompliance, or chronic rejection.
Yet, the proof of concept of these procedures has been
established with favorable intermediate and long-term
success. 6 , 7 There have been growing efforts in the United
States and the rest of the world toward wider application
of reconstructive transplantation, and many centers are
establishing vascularized composite allograft programs.
Thus, the outlook for reconstructive transplantation seems
promising, but long-term predictions on outcomes are not
yet possible.
This chapter is organized into three sections focusing
on the past, present, and future of this groundbreaking
specialty.

38 • CHAPTER 4
EVOLUTION OF RECONSTRUCTIVE
TRANSPLANTATION
History
The earliest reports of tissue and organ transplantation,
including that of the heart, date to between the second
centuries BCE and CE in China. 8 Restoration of mutilat-
ing injuries of the nose and ear with pedicled autografts
from the forehead, neck, and cheek are discussed in the
Sušruta Samhita . 9 – 11 This treatise, written by the Indian
surgeon Sušruta who lived around 480 BCE, describes
in detail the techniques of rhinoplasty. Although this was
the fi rst credible account of reconstructive transplantion,
mythology credits the patron saints Cosmos and Damian
with performing the fi rst limb allotransplantation about
870 years later. 12 – 15 Per the legend, around the year 348,
they transplanted the right leg of a dead Moor onto a
patient after amputating his gangrenous leg. Similar leg-
end is also depicted in a fi fteenth century fresco in the
St. Julius Basilica in Milan, showing St. Julius replanting
the amputated thumb of a man. 16 In the sixteenth century,
the Italian surgeon from Bologna, Gaspare Tagliacozzi,
described a method of nasal and aural alloreconstruction
in his book De curtorum chirurigia per insitionem ( On the
Surgery of Mutilation by Grafting ). 17 – 19 He used skin from
the inner aspect of the arm from a slave to reconstruct the
nose of a wealthy patient who injured it during a sword
fi ght. Unsubstantiated reports indicate that the recon-
structed nose allegedly survived for 3 years after which the
donor fl ap was rejected. In his book, Tagliacozzi concludes
that allografts are possible, but the binding of tissues to one
another for a suffi cient length of time was prevented by a
“force and power.” This was possibly the earliest reference
to immunologic phenomenon of allograft rejection, as we
now know it.
During the next three centuries, the focus of organ
transplantation was technical and led to advancements in
antisepsis, anesthesia, hemostasis, and organ preservation.
However, the most important challenge to replacing tissues
or transferring a body part from one person to another lay
in graft revascularization. Alexis Carrell in 1902 described
the surgical technique of vascular anastomosis, thus lay-
ing the foundation for conventional vascular surgery. 20 – 22
However, he failed to achieve permanent graft acceptance.
Carrell attributed this “organ failure” to vascular compli-
cations because he had no knowledge of the process of
rejection.
The problem of rejection began to be realized clini-
cally in the twentieth century when allografting became
the model for research. In 1900, Karl Landsteiner and
C. Philip Miller were the fi rst to recognize that humans
could be grouped according to the presence of agglutinins
in their sera. They eventually discovered ABO, Rh, and
other red cell antigens and laid the foundation for histo-
compatibility testing. 23 In 1924, Emile Holman recognized
that a single donor’s skin graft rejected more rapidly on
the second application. 24 This observation was eventually
referred to as the second set phenomenon and, as a result,
some believed allografting to be a useless and fruitless
endeavor. Meanwhile, other scientists were studying the
biologic aspects of transplantation. In 1932 and 1937, the
fi rst attempts at skin grafting were performed between
identical twins. 25 , 26 In 1937, Peter Alfred Gorer discov-
ered the fi rst histocompatibility antigen in humans 27 and
established the concept of “self vs nonself” after realizing
that antigens on tissue cells are genetically determined
and capable of eliciting foreign graft destruction. In 1943,
Peter Brian Medawar, a young zoologist in Britain, had
made the historic discovery rejection. 28 Investigating skin
grafting in rabbits, he differentiated between immune
responses to homografting and autografting. He also
made the observations that skin grafts from a family
member were better tolerated than those from an unre-
lated donor, and those skin grafts from an identical twin
were better tolerated than from other family members.
Medawar subsequently described the basic characteristics
of the immune response—recognition, destruction, and
memory.
In 1944, Richard Hall described the technical aspects of
cadaveric upper extremity transplantation, including the
need for surgical team expertise with organ preservation,
bone fi xation, and microsurgery as well as availability of
appropriate facilities, but there was no mention of rejec-
tion. 29 Ironically, Hall had no knowledge of the work of
Landsteiner, Gorer, or Medawar.
Following Medawar’s groundbreaking fi ndings in skin
grafting, 30 other signifi cant breakthroughs led to the foun-
dations of modern organ and reconstructive transplan-
tation. These include the discovery of leukocyte blood
groups in humans by Jean Dausset in 1952. 31 Dausset
recognized that individuals who had received multiple
blood transfusions had leukoagglutinins in their sera,
whereas those who had received few or no transfusions
had no isoagglutinins in their sera. This important distinc-
tion led to the accurate conclusion that alloantibodies, as
well as autoantibodies, exist, and it paved the way for dis-
covery of the human leukocyte antigen (HLA) locus in
humans. In the 1950s, Simonson and Mitchison observed
that acute rejection was not mediated by antibodies but
by lymphocytes. 32 , 33
Building on Holman’s preliminary work, Medawar in
collaboration with Thomas Gibson, a plastic surgeon, is
credited with establishing the fi rst reliable animal model
for the second set response. 34 However, attempts at skin
allotransplantation were repeatedly unsuccessful, leading
investigators to other areas of transplantation. In a land-
mark procedure, another plastic surgeon, Joseph Murray,
in association with his colleagues Merrill and Hartwell,
performed the fi rst kidney transplant between identical
twins in 1954. 35 – 39 Following this, in 1959, the fi rst suc-
cessful composite tissue allograft was performed by yet
another plastic surgeon, Erle Peacock who transplanted a
digital fl exor tendon mechanism en bloc. 40 , 41 Indeed, it was
Peacock who coined the term “composite tissue allograft”

RECONSTRUCTIVE TRANSPLANTATION: EVOLUTION, EXPERIENCE, EMERGING INSIGHTS • 39
to differentiate these transplants that were composed of
modules of multiple tissues unlike solid organs.
It was not until the 1960s and 1970s, though, that dis-
parity at the major histocompatibility complex (MHC)
was recognized as a genetic basis for rejection. In 1964,
Paul Terasaki 42 developed the microlymphocytotoxicity
test to detect preformed circulating cytotoxic antibodies
in recipients. In the same year, Roberto Gilbert Elizalde
performed the fi rst hand transplantation in Guayaquil,
Ecuador. 43 , 44 However, Gilbert did not have insight into
the immunology of skin-containing grafts, such as hand
transplants, as well as access to effective pharmacologic
immunosuppression. The combination of prednisone and
azathioprine could not prevent acute rejection of the
transplanted hand in 14 days that had to be re-amputated.
This bold and pioneering attempt at hand transplantation
underscored the need to understand the immunology of
composite grafts as well as improve immunosuppressive
strategies to prevent or treat acute rejection.
Immunosuppression
It is only the knowledge gained from landmark discoveries
in the past century that facilitated the manipulation or sup-
pression of the immune response, allowing successful pro-
longation of graft survival. After Medawar’s demonstration
that rejection was an immunologic event, the next logical
question was: Why not prevent this phenomenon by sup-
pressing the immune system? The innovation of induced
immunosuppression in the setting of transplantation is
credited to John Loutit, who in the 1950s experimented
with total body irradiation in rodents undergoing skin
grafting. 45 In 1958, this form of immunosuppression was
applied to humans by Murray in Boston and Hamburger
in Paris. 38 , 46 , 47 Graft survival improved, but was still dis-
mal because these drugs acted indiscriminately and were
associated with severe organ-specifi c and systemic adverse
effects.
Success was rare until the era of pharmacologic immu-
nosuppression. The introduction and application of
the antimetabolite 6-mercaptopurine by Schwartz and
Dameshek and Zukoski and Calne dramatically changed
the course of early attempts at organ transplantation. 48 – 50
Wider clinical use came with the development of a precur-
sor drug, azathioprine (Imuran) by Hitchings and Elion. 51
It was Murray and Calne who fi rst used it clinically in
1962. 52 , 53 Since 1962, all transplantation of organs and tis-
sues between unrelated individuals has been performed
under pharmacologic immunosuppression. The last third
of the twentieth century witnessed the realization of liver,
heart, lung, pancreas, and small bowel allotransplantation
as drug protocols were fi ne-tuned. 54
The 1960s and 1970s saw the advent of polyclonal anti-
body technology, followed by cyclosporine and monoclo-
nal antibodies during the 1980s. Cyclosporine dramatically
changed the science and the practice of transplantation by
increasing dramatically allograft survival, which made it
possible for widespread clinical application of extrarenal
transplantation. 55 – 57 The FDA approved cyclosporine A for
use in the United States in 1983. The calcineurin inhibi-
tor tacrolimus (FK 506) was discovered in 1987, 58 clinical
trials were conducted in 1989, 59 and FDA approval came
in 1994. Tacrolimus led to dramatic improvements in
solid organ transplantation, 60 – 63 allowing highly immuno-
genic grafts such as the small bowel to be transplanted. 64 – 66
The success of the calcineurin inhibitors cyclosporine
A and tacrolimus made them the cornerstone drugs of
the modern era of transplantation. 54 The 1990s saw the
introduction of novel drugs such as the antimetabolite
mycophenolate mofetil 67 (approved by the FDA in 1995)
and rapamycin 68 (sirolimus, discovered in 1976 but FDA
approved only in 1999). Combining these drugs with a cal-
cineurin inhibitor 69 – 73 signifi cantly reduced acute rejection
and improved solid organ graft survival with a reduction in
adverse effects.
Current immunosuppressive regimens are a far cry
from the rudimentary combination of prednisone and
azathioprine used in the 1960s. But things are changing
with the realization that these advances are tempered by
drug toxicities, leading to considerable morbidity and even
mortality. The use of calcineurin inhibitors, the dominant
paradigm for the past two decades, is being challenged as a
result of the long-term effects of these agents on allografts.
Investigators and clinicians alike are also looking to avoid
corticosteroids that have been the mainstay of immuno-
suppressive regimens, and to minimize global immunosup-
pression after transplantation.
Immunology
Plastic surgeons have been intimately involved in the evo-
lution of organ transplantation. Although Gibson, Peacock,
and Murray made equally signifi cant contributions, it was
Murray who earned the coveted recognition of being the
fi rst and only plastic surgeon to date to receive the Nobel
Prize in Medicine. 74
However, as a specialty, our understanding of the
immunologic behavior of allografts lagged behind techni-
cal developments in surgery. Much knowledge concerning
the immunologic aspects of reconstructive transplantation
has been gained from studies in small and large animal
models.
Vascularized composite tissue allografts (CTAs), such as
hand or face transplants, differ from solid organ transplants
in several important aspects: 75 (1) CTAs are composed of
tissues derived from multiple germ lines such as ectoderm,
endoderm, and mesoderm such as skin, muscle, blood ves-
sels, nerve, fat, cartilage, bone, and bone marrow; (2) the
functional allograft is easily and grossly visible for inspec-
tion by the patient and clinical management team; and
(3) for the most part, CTAs are not strictly life-sustaining.
Transplantation of multiple tissue constructs such as
CTAs is associated with a quantitatively graded recipi-
ent immune response to individual graft components.

40 • CHAPTER 4
Traditionally, skin has been considered the most immuno-
logically diffi cult allograft to transplant. This impression
has been verifi ed experimentally. Skin, subcutaneous tissue,
muscle, bone, nerve, and blood vessels have been evaluated
for their intrinsic and relative antigenicities. 76 Skin is the
most immunogenic component, and it usually triggers and
is the target of acute rejection. 77 Following skin, muscle,
bone, cartilage, and nerve predictably induce a relatively
lower immune response in that order.
Skin is the largest organ and is both a physical and
immunologic barrier. 78 , 79 Due to its exposure to the envi-
ronment, the skin, like the small bowel and lung, has a
robust and effective local immune system, called the skin
immune system, which contributes to its heightened anti-
genicity. 80 , 81 Langerhans cells are immature dendritic cells
that are the primary dermal antigen presenting cells. They
are extremely effi cient at initiating innate responses to trig-
ger sensitization and priming of naïve host T cells to attack
the graft. Langerhans cells make up 2% to 4% of epider-
mal cells. Keratinocytes make up 90% of epidermal cells
and play an accessory role in initiating or supporting cell
mediated immune responses. Apart from Langerhans cells,
skin also has other types of dendritic cells such as dermal
dendritic cells. 82 These dendritic cells, due to their migra-
tory capability, can carry antigenic information from skin
to secondary lymphoid organs and present to lymphocytes
for priming and stimulation. 83 , 84 Human skin also has tis-
sue specifi c minor antigens that may contribute to its anti-
genicity. 85 These are similar to antigens such as Skn and
embryonic prealbumin 1, which are potent contributors to
skin antigenicity in murine models and swine models. 86 , 87
Skin antigenicity correlates with clinical fi ndings in
reconstructive transplants. It initially shows the fi rst signs
of rejection and is associated with maximal cellular infi l-
trate in established rejection. 88 , 89 Experimentally, it has
been possible to induce tolerance toward all tissues of a
CTA except the skin (split tolerance). 90 More powerful
conventional/standard immunosuppression regimens have
successfully treated skin rejection and prolonged CTA
graft survival; but, like other allografts, in most cases, stan-
dard baseline immunosuppression is still unable to prevent
long-term skin rejection/deterioration. Although other tis-
sues are less antigenic, rejection of even one component of
a CTA could result in graft dysfunction or compromise.
The gross visibility and accessibility of CTAs, such as
reconstructive transplants, enables direct visual inspection
with comparison to nonallograft tissues for routine clini-
cal evaluation, directed biopsy, and topical therapy. This
potentially enables more localized therapy, and possibly,
reduced systemic exposure to standard immunosuppres-
sive medications, lessening side effects for recipients, who
for the most part, are healthy. 91
Reconstructive transplants differ from all other solid
organ grafts in regard to bone marrow content. No other
solid organ graft carries an intact vascularized bone/bone
marrow environment/component. Liver grafts do possess
signifi cant hematopoietic potential and intestinal grafts
carry a heavy mature lymphocyte burden due to the
presence of the gut-associated lymphoid tissue, but neither
contains functional bone marrow. Both of these organs
have produced cases of graft-versus-host disease (GVHD)
in transplant recipients and with both organs fatal cases
of GVHD have been reported. 92 , 93 When bone marrow or
hematopoietic stem cells are transplanted for treatment
of malignancy, GVHD is quite commonly seen and is fre-
quently a severe, life-threatening disease. Composite tissue
grafts containing bone marrow and lymph node compo-
nents carry the potential for producing GVHD, but no epi-
sodes have been reported to date in clinical reconstructive
transplantation. The unique presence of vascularized bone
marrow within its intact microenvironment facilitates the
implementation of tolerogenic or immunomodulatory
strategies in reconstructive transplantation unlike in any
other solid organ.
Another major difference between solid organ grafts
and reconstructive transplants is the relative level of expo-
sure to the environment. Lung and intestine transplants
are exceptional in that they are constantly exposed to
environmental factors and both have proven to be highly
prone to bacterial, viral, or fungal infections. 94 , 95 These
infections have compromised the survival of both of these
grafts and appear to signifi cantly limit success rate in these
transplants. It was thought that reconstructive transplants
would be subject to infections as well due to constant
environmental exposure, especially if the integrity of the
skin component was compromised by graft rejection and/
or injury. Fortunately, this has not been the case. No recon-
structive transplants performed to date have reported any
serious infection in the graft itself. Some infections have
been reported in the recipients but these have most often
been the infections encountered in all immunosuppressed
patients, eg, cytomegalovirus (CMV) infection. Although
the recipients of reconstructive transplants are immu-
nosuppressed and are subject to the opportunistic infec-
tions frequently encountered in all transplant populations,
environmental exposure does not appear to increase the
incidence of infection in these grafts.
EXPERIENCE WITH RECONSTRUCTIVE
TRANSPLANTATION
Program Establishment and Organization
Implementing a reconstructive transplant program poses
tremendous challenges. Solid organ transplantation is
a time-tested procedure and is now standard of care.
Reconstructive transplantation on the other hand is an
emerging specialty that is the amalgamation of the sci-
entifi c principles of reconstructive surgery and the con-
cepts of organ transplantation. Thus for any reconstructive
transplant program to be successful, it must be collabora-
tion between a multidisciplinary team comprised among
others of a core group of hand and transplant surgeons
( Figure 4-1 ). Such a joint effort can overcome the chal-
lenges that are inherent in a complex therapeutic option
that integrates multiple specialties during the planning,

RECONSTRUCTIVE TRANSPLANTATION: EVOLUTION, EXPERIENCE, EMERGING INSIGHTS • 41
Institutional review board or ethics board review ensures
a thorough informed consent process, sound research design
with data monitoring, qualifi ed investigators/researchers,
favorable risk/benefi t analysis, and equitable selection of
subjects. The consent process must be
• Comprehensive—includes research procedure, pur-
pose, risks, benefi ts, alternatives, etc
• Customized—functions of intelligence, rationality,
maturity, and language skills; presentation of infor-
mation must be adapted to the patient’s capacity
• Voluntary—requires conditions free of coercion and
undue infl uence
Study compliance or oversight is usually accomplished
by an independent data safety monitoring board composed
of specialists, statisticians, ethicists, and psychologists.
It is very important to obtain the support of the local/
regional OPO for the program. The roles of the OPO
relate but are not limited to facilitation of donor screening,
evaluation, and selection, donor family education and con-
sent, graft procurement/acquisition/allocation, and donor
transportation logistics.
Lastly, given that reconstructive transplant procedures
are emerging, innovative, and novel, they are high profi le
and media intensive in nature. Thus, public relations are an
important consideration for every program.
This is important for timing and coordination of press
releases, protection of donor identity and patient confi den-
tiality, and announcement of positive or negative outcomes.
The media services in the institution can help with website
design and planning, distribution of study material, press
releases, preparing team members for briefi ngs and video
and photographic coverage, and archival of procedures.
Patient and Procedural Considerations
Proper screening evaluation, selection, and management
of donors and potential recipients are very important for
successful outcomes in reconstructive transplantation.
Decades of experience with solid organs have allowed us
to establish criteria for donor and recipient selection. In a
novel fi eld like reconstructive transplantation, parameters
for inclusion and exclusion of donors and recipients have
not yet been conclusively defi ned nor standardized and
such criteria as well as technical considerations vary by
type of transplant, eg, hand, face, etc. 98 , 99
Most of the criteria used for donor selection are similar
to that in organ transplantation. These include histocom-
patibility testing for tissue matching and blood cross-
matching (cross-match negative). The ideal patient is a
donor who is a nonsmoker in good health with no history
of drug abuse or trauma to the graft to be procured, and
whose age matches as closely as possible with the recipient.
Specifi cally, the transplant donor is selected after matching
for sex, color, tone of skin, age, and comparable phenotypic
characteristics of the recipient. Figure 4-3 shows a donor
hand graft following retrieval. Absolute contraindications
FIGURE 4-1. The reconstructive transplant
multidisciplinary team.
Ortho/Plastic hand
Microsurgery
OPO
Infectious
diseases
Psychiatry
social work
Occupational
therapy
Reconstructive
transplant program
Transplant surgery &
transplant pathology
Immunology
Team composition and expertise
FIGURE 4-2. Team coordination and collaboration.
Other specialties
Core team
• Team leader
• Director
• Coordinator
• Recipient team
• Donor team
• Anesthesia team
Surgical team
Ancillary team
• Psychiatry
• Physical therapy
• Pathology
• Immunology
• OPO
• Other specialties
Team coordination and collaboration
personnel, procedural and post-transplant phases. The core
team is composed of a team leader, scientifi c director, and
program coordinator who orchestrate the complex trans-
plant logistics in conjunction with the surgical team and
the ancillary team ( Figure 4-2 ).
The key steps in the planning and preparation for
a reconstructive transplant program are institutional/
organizational support, completion of an exhaustive fi s-
cal analysis, organizational or extramural fi scal assurance
or strategies for such support, completion of regulatory
review and approval, provision for study compliance
and oversight, evaluation of infrastructure, facilities and
resources, presence of a multidisciplinary team with appro-
priate expertise, agreement on a protocol for transplant,
and organ procurement organization (OPO) support and
collaboration. 96 , 97

42 • CHAPTER 4
are history of previous malignancy, viral hepatitis (B or
C), or viral infections such as HIV. The presence of sero-
positivity for CMV or Epstein-Barr virus (EBV) is not a
contraindication for donor selection; however, antiviral
prophylaxis is indicated in CMV seronegative recipients
receiving transplants from such donors.
Recipients younger than 18 years of age are not consid-
ered to be adults, and, therefore, there are issues of informed
consent in an experimental procedure. Furthermore, pedi-
atric patients are more likely to develop immunosup-
pressive-related complications, such as post-transplant
lymphoproliferative disease, than adults. 100 Recipients
over the age of 65 are usually not considered by programs
because of increased immunosuppression-related compli-
cations, limited years of potential gain from the transplant,
and decreased nerve regeneration. Medical screening of
recipients includes a complete medical history and physi-
cal examination; routine laboratory studies; blood typing
and cross-matching; HLA typing; testing for panel-reactive
antibodies; and serology for EBV, CMV, HIV, and viral
hepatitis. Other tests include radiography, Panorex imag-
ing, angiography (to exclude abnormal vascular patterns),
ultrasound, electromyography, nerve conduction velocity,
MRI, and functional MRI as relevant. Reconstructive trans-
plantation, unlike organ transplantation, is usually limited
to healthy patients. A patient who is in renal, cardiac, pul-
monary, or hepatic failure is excluded whether previously
transplanted with solid organs or not.
A thorough assessment of body image adaptation, includ-
ing the psychological meaning of the transplant to the can-
didate, the psychological impact of the disfi gurement or
defect on identity and relationships, coping/adjustment
to the injury, motivation for transplantation, anticipated
comfort with the transplant, prosthetic use and phantom-
limb sensation (in hand transplants) is performed in all
candidates. 101 Evaluation of the total family support sys-
tem is also important. The apparent ideal candidate with-
out family support is not an ideal candidate. These patients
will be dependent on a positive family structure, certainly
within the fi rst 6 months if not for the life of the trans-
plant. A family support system that does not encourage
FIGURE 4-3. Donor hand graft after harvest, before
transplantation.
strict adherence to the rigorous postoperative regimen
will fail. This rigorous regimen includes physical therapy,
timely compliance with medications, repeated medical
assessments, and avoiding certain activities and substances
that may increase the risk of immunosuppressive-related
complications. The degree of expectations concerning the
transplant outcome and the recognition of the experimen-
tal/investigational nature of these procedures are also esti-
mated. Finally, the level of personality strength, including
coping skills and regression, are assessed. An additional
objective perspective regarding the pros and cons of the
particular transplantation is provided (independent of the
transplant team) to the recipient through a “patient advo-
cate” who is a respected peer from the home community
of the recipient. It is beyond the scope of this chapter to
elucidate how this delicate decision is made. Psychological
criteria are used to evaluate the competency of recipients
to comply with the rigorous pre- and post-transplant reha-
bilitation program or drug regimens for the rest of their
lives.
Programs must cover or ensure coverage of lifelong costs
of immunosuppressive medications and other expenses
related to post-transplant management of recipients,
including complications. Some programs may exclude
patients without insurance and/or fi nancial security dur-
ing the selection process. It has been argued that enroll-
ing patients on the premise of paying for all postoperative
medications and management of complications raises the
issue of moral hazard related to monetary enticement for
transplantation.
Protocol Related Aspects
The current immunosuppressive protocols applied to
reconstructive transplantation are extrapolated from
regimens used in solid organ transplantation. The overall
amount of immunosuppression required to ensure graft
survival is comparable with that used in renal transplanta-
tion. Such conventional immunosuppression has resulted
in patient and graft survival that is 100% at 1 year after
upper extremity transplantation and 87% after face trans-
plantation. 101 The majority of transplant patients received
either polyclonal (antithymocyte globulins) or monoclo-
nal (alemtuzumab, basiliximab) antibody preparations as
induction therapy followed by high-dose, triple-drug com-
bination for maintenance therapy, including tacrolimus,
mycophenolate mofetil, and steroids, although the doses
and trough levels of each drug differed between some cen-
ters. Such regimens have proved suffi cient to prevent early
immunologic graft loss but were not able to prevent acute
rejection. Some programs follow steroid avoidance regi-
mens while others rely on monotherapy immunosuppres-
sion. Successful reversal of acute rejection episodes has
been achieved using topical clobetasol or tacrolimus oint-
ment with or without short-term bolus steroid doses. 102 , 103
Acute rejection is a T cell and/or antibody-mediated
attack of the transplant by the recipient’s immune system
resulting in damage and ultimately loss of the graft. The

RECONSTRUCTIVE TRANSPLANTATION: EVOLUTION, EXPERIENCE, EMERGING INSIGHTS • 43
skin has been demonstrated to be the prime target of rejec-
tion and monitoring of the skin by inspection is therefore
considered most important for monitoring. Protocol graft
skin or mucosal biopsies must be routinely performed
until the fi rst year plus whenever clinically indicated
(visible signs of rejection such as a maculopapular rash).
Biopsy samples may be analyzed by means of histology
and immunohistochemistry (staining for CD3, CD4, CD8,
CD20, and CD68) for quantifi cation and characterization
of cellular infi ltrates. Scoring for severity of acute rejection
is accomplished using established standard grading crite-
ria, such as the Banff classifi cation. 104 , 105 Important clinical
characteristics of acute rejection include edema, erythema,
escharifi cation, and necrosis. Biopsies must also be exam-
ined for evidence of chronic rejection, including intimal
hyperplasia and subintimal foamy histiocytes in the vessels
of the skin or muscle and tissue fi brosis.
Recipient and donor cells must be typed pretrans-
plant for HLA. 106 , 107 Additional DNA samples from
recipient/donor must be stored for future typing for MICA
(MHC class I chain A related) genes in those patients in
whom anti-MICA antibody is detected. All sera should be
screened by antihuman globulin-enhanced complement-
dependent cytotoxicity assays, by enzyme-linked immu-
nosorbent assay (to identify immunoglobulin G anti-HLA
class I– and class II–specifi c antibodies independently), and
by Luminex (allows for the identifi cation of anti-MICA
antibodies, as well as ascertainment of their donor specifi c-
ity). The MICA and MICB antigens are expressed on the
surface of endothelial cells and epithelial cells and elicit
a strong antibody response in recipients of solid organ
transplants. Cell-mediated immunity may be measured
by the ImmuKnow assay that detects adenosine triphos-
phate (ATP) synthesis in CD4 cells. Immune responses
are reported in ng/mL of ATP and categorized as strong
(.525), moderate (226–524), or low (,225). The desir-
able target zone for all transplant recipients is 280 ng/mL
ATP with a 96% negative predictive value for rejection or
infection. An outline of the procedures and protocols used
in reconstructive transplantation are listed in Figure 4-4 .
FIGURE 4-4. Procedures and protocols used in
reconstructive transplantation.
Preoperative
• Screening | Evaluation | Selection
• Donor and recipient logistics
• Consent | Enrollment | Listing
• TICU and inpatient management
• Immunosuppression | Immunomonitoring |
OT regimens
• Team activation | Coordination | Allocation
Intra-perioperative
Postoperative
Procedures | Protocols
World Experience
Over the past two decades, reconstructive transplanta-
tion has emerged as a new fi eld, with hand, face, and other
transplants being performed around the world at mul-
tiple centers. 1 , 91 The overall world experience counts 70
hands transplanted in 50 recipients and 15 face transplants.
Good functional results have been achieved with excel-
lent patient satisfaction, acceptably low morbidity, and no
mortality. 7
The fi rst American patient has the longest surviving
hand transplant 13 years after surgery. 6 There have been
exceptions to this encouraging record. These include the
fi rst French patient 108 and the discouraging Chinese expe-
rience. 109 Bilateral hand transplants performed in conjunc-
tion with face transplants were lost to complications in
two cases in Amiens, France and Boston. One patient in
Louisville, Kentucky lost his graft to chronic rejection. 110
In some of the above-mentioned cases, transplanted hands
were amputated more than 2 years after transplantation.
These cases have shown that the operation is fully revers-
ible. More importantly, re-amputation provided an oppor-
tunity to observe the evolution of untreated acute rejection
in the event of noncompliance, treatment withdrawal, and
early chronic rejection.
Since 2005, 15 facial transplantations have been per-
formed in fi ve different centers in three countries. Four
teams have reported their outcomes in separate publica-
tions. Overall, long-term function of facial grafts has been
reported in seven cases with good sensory and motor
recovery. Functionality reported in patients included lip
and dental occlusion, phonation, olfaction, gustation,
mastication, and endobuccal pressure. Sensory return
was also seen in the majority of patients with recovery
of protective, fi ne touch, vibratory, and temperature
sensation.
EMERGING INSIGHTS
Chronic Rejection
Unlike acute rejection, we are as yet unclear regarding
the magnitude of risk for chronic rejection or how it man-
ifests in reconstructive transplants, but there is enough
experience with animal models and other solid organs
that manifestations can be reasonably and accurately
predicted.
In solid organ transplantation, both immunologic and
nonimmunologic factors play roles in chronic rejection
pathogenesis ( Table 4-1 ). 111 Immunologic risk factors, are
by far, the more important for all allografts. Include are
the frequency, severity and temporal onset of acute rejec-
tion, greater HLA mismatch, panel reactive antibody sta-
tus of recipient, racial mismatch between donor/ recipient
(eg, Caucasian donor into non-Caucasian recipient);
sex mismatching (female donor to male recipient and
vice versa); and CMV seromismatch (CMV 1 donor to
CMV 2 recipient), listed largely in order of infl uence.

44 • CHAPTER 4
Data from almost every form of solid organ transplantation
have indicated decreased graft survival in the face of CMV
infection. 112 CMV infection has a far greater effect on the
allograft than on native organs, increasing the risk of both
acute rejection and chronic rejection. 113 This is engendered
by cytokines, chemokines, and growth factors.
Chronic rejection may begin weeks to months after trans-
plantation, especially if there are many high-grade acute
rejection episodes. In kidney transplants, late, severe, or per-
sistent acute rejection episodes occurring more than 1 year
after transplantation are particularly strong and consistent
predictors of chronic rejection. 114 The acute rejection may
be predominantly cellular or antibody mediated. Antibody-
mediated rejection has a considerably worse prognosis than
acute cellular rejection. 115 Thus, in kidney transplants, severe,
late-onset acute rejection with a signifi cant humoral compo-
nent may be more predictive of chronic rejection. However,
such a correlation may not be totally valid in other organ
transplants. For example, in liver transplants, early, mild acute
rejection and late episodes of acute rejection are usually not
associated with later chronic rejection. 116
Late-onset acute rejection may be seen in inade-
quately immunosuppressed or noncompliant patients. 117
Medication noncompliance accounts for one third of
late-graft losses and is an important factor contribut-
ing to chronic rejection. Though the exact determinants
are unclear, some factors associated with noncompliance
include inadequate physician–patient relationship, long
duration after transplant surgery, multiple immunosup-
pressive medications, nontolerance of medications, missed
clinic visits, and poor transplant outcomes. 118
Common histopathologic features of chronic rejection
in solid organs include (a) patchy organized (lymphoid
neogenesis) interstitial infl ammation; (b) patchy intersti-
tial fi brosis and associated parenchymal atrophy; (c) graft
vascular disease, which primarily manifests as concentric
fi brointimal hyperplasia of arteries; (d) destruction of epi-
thelial-lined conduits; and (e) destruction and atrophy of
organ-associated lymphoid tissue and lymphatics. 119
FIGURE 4-5. Chronic rejection leading to progressive
ischemia.
Intimal thickening
Lumen
Intimal thickening
Lumen
A
B
Hand transplant recipients, to date, have been moni-
tored for chronic rejection by clinical and functional
exams, skin biopsies, digital subtraction angiography,
and standard vascular imaging. The Louisville team has
reported 110 the loss of the transplant in their fourth
patient to ischemia secondary to progressive Campath 1H
confi rmed on histopathology ( Figure 4-5 ). Conventional
testing failed to reveal any evidence of chronic rejection
but deep tissue biopsies were positive for Campath 1H
in all of their other patients (Dr. Warren Breidenbach,
personal communication). The team concluded that the
incidence and severity of Campath 1H correlated with
cellular and humoral parameters as well as the immu-
nosuppression load. This is the fi rst conclusive report
of chronic rejection–related fi ndings in clinical recon-
structive transplantation. There is also a similar report
of Campath 1H leading to loss of CTA wherein chronic
allograft vasculopathy was seen in vascularized knee
transplantation. 120 Within 5 years, 100% of the grafts were
lost. Histopathology confi rmation of the cases revealed
“diffuse concentric fi brous intimal thickening and occlu-
sion of graft vessels.” The authors agree that the “lack of
TABLE 4-1. Chronic Rejection Factors
Immunologic
Non-Immunologic
Timing of AR (late vs
early)
Older donor
Severe, repetitive,
humoral AR
Donor atherosclerosis
Greater HLA mismatch
Cadaver donor
Higher PRA of recipient
Prolonged cold ischemia
CMV 1 Donor to CMV
2 Recipient
Hypertension, DM, Obesity,
High cholesterol
Steroid resistant AR
Unstable donor
Antidonor antibodies
1 C4D
Non-compliance

RECONSTRUCTIVE TRANSPLANTATION: EVOLUTION, EXPERIENCE, EMERGING INSIGHTS • 45
adequate tools for monitoring graft rejection might have
allowed multiple untreated episodes of acute rejection,
triggering myointimal proliferation and occlusion of graft
vessels” and that “adequate tools for monitoring need to
be developed.” It seems clear that these extremities were
lost secondary to Campath 1H, and this must be consid-
ered a possible chronic rejection. The inability of conven-
tional techniques to monitor and diagnose Campath 1H
as the primary predictor of chronic rejection is concern-
ing and has implications for long-term outcomes after
reconstructive transplantation.
At this point, we do not conclusively know if fac-
tors that play a role in genesis of chronic rejection in
solid organs also mediate the phenomenon in recon-
structive transplantation, but the expectation is that the
pathophysiology will be similar. With prolonged survival
of reconstructive transplants beyond 10 years, we will
inevitably see more grafts develop signs of chronic rejec-
tion or succumb to chronic rejection. We will then be
able to better defi ne, diagnose, and grade this condition.
Meanwhile, we are limited to minimizing the known
risk factors (from solid organ experience) that may con-
tribute to a postulated increase of chronic rejection in
reconstructive transplants and also invest collective sci-
entifi c intellect into identifying novel diagnostic tools
and therapeutic strategies to monitor and possibly treat
chronic rejection.
Cortical Reorganization
A unique phenomenon observed after reconstructive
transplantation of the hand or face is the reassignment
of portions of the recipient’s brain in the sensorimotor
cortex to control the graft. This is called “re-organization”
or “plasticity” of the brain. Both the hand and face are
contiguously represented in the homunculus. For exam-
ple, previous studies have demonstrated that changes
FIGURE 4-6. Functional MRI demonstrating neural
integration of the transplanted limb into the premotor cortex.
in cortical organization of the homunculus occur after
amputation. However, the impact of limb transplantation
on spatial reorganization of the motor cortex is just now
being revealed. 121 , 122 After a hand is amputated or the face
is subjected to devastating injury, the area of the brain
that was receiving signals from the hand or face is gradu-
ally lost and is taken over by other functions. However,
after a hand or face transplant, that area of the brain can
reestablish its original function, and the signals from the
new hand or face go back to the area of brain that was
used to control the original area. Such neural integra-
tion of the transplant into the premotor cortex has been
demonstrated using functional magnetic resonance imag-
ing ( Figure 4-6 ), diffusion tractography, or magnetoen-
cephalography studies. This phenomenon has not been
reported after organ transplantation. Figure 4-7 shows
high- defi nition fi ber tracking imaging before and after
transplantation demonstrating reintegration of nerve fi ber
inputs to the sensory motor cortex.
FIGURE 4-7. High-defi nition imaging of neural fi ber inputs into the sensory cortex:
(A) pre-transplant; (B) post-transplant.
B
A

46 • CHAPTER 4
Strategies for Reduction or
Elimination of Immunosuppression
Despite the excellent results thus far, the full potential
and clinical applicability of reconstructive transplantation
has not yet been realized because of the hazards associ-
ated with the long-term use of immunosuppressive drugs.
Modern research into mechanisms of immune tolerance
offers the promise of reprogramming the immune system,
so as to harness the body’s natural tolerance mechanisms
in the service of graft acceptance. This would allow the
minimization of immunosuppressive treatment and offers
the prospect of eventually weaning transplant recipients
off their drugs.
Fifty years ago, Medawar and colleagues demonstrated
transplantation tolerance elicited by infusion of foreign
marrow into a newborn mouse. 123 This was the fi rst dem-
onstration of acquired immunological tolerance, and as
such, offered a challenge for achieving transplantation
tolerance as a clinical goal in an immunologically mature
adult—a goal yet to be realized as a routine procedure.
Medawar’s experiment was used as evidence to support the
clonal selection theory and the notion that self-tolerance
arises from purging of self-reactive lymphocytes from
the immune repertoire. Later studies demonstrated that
marrow infusions provided a source of stem cells able to
establish a state of mixed (both recipient and donor) blood
chimerism. This would guarantee a permanent source of
donor antigen to ensure continuous purging of alloreactive
lymphocytes, so setting the stage for current concepts of
inducing tolerance therapeutically.
Tolerance can be defi ned as the indefi nite acceptance of
the grafted tissue after only a short course of immunomod-
ulatory treatment. These fi ndings have galvanized efforts
to achieve tolerance in the clinic, although this is proving
a formidable task. The goal of achieving clinical tolerance
“up front” is enormously challenging, given the genetic
heterogeneity of donor/recipient combinations and prior
priming of the immune system to environmental anti-
gens, which cross-react with those of the donor organ. 124
Furthermore, continuing improvements with immunosup-
pressive drugs that produce good medium-term outcomes
make it diffi cult to introduce new “tolerance” protocols
that risk loss of the transplanted organ. The emerging com-
promise has been to aim at harnessing tolerance mecha-
nisms as a means of minimizing the dose and number of
drugs administered. 125
Some of the strategies for immunosuppression mini-
mization or allograft tolerance include approaches using
donor bone marrow transplantation or inducing peri-
transplant depletion of recipient T cells. The mixed chi-
merism model involves induction of allograft tolerance
by establishing long-term mixed chimerism, a state in
which both donor and recipient hematopoietic cells
coexist after engraftment. 126 One of the lymphocyte
depletion approaches includes the use of Campath 1H,
which is an antibody that binds to the CD52 receptor,
critical for T cell function in humans. Campath 1H leads
to depletion of T cells, B cells, and monocytes, but spares
bone marrow stem cells. Early trials with Campath 1H
in renal transplants demonstrated that allograft survival
could be prolonged but with low doses of maintenance
immunosuppression. 127 Campath 1H induction has been
implemented in a few hand transplant programs with suc-
cessful reduction of maintenance immunosuppression.
Such a state of tolerance is called “prope tolerance” or
“tolerance lite.” 125
Over the past fi ve decades, more than 50 different
methods of tolerance induction have succeeded in small
or large animal models. Yet tolerance protocols have not
widely replaced immunosuppression in clinical organ
or reconstructive transplantation. The reason for this is
straight forward. Many of the tolerance protocols are too
risky for clinical application. In other protocols, the risks
remain unknown. Therapies designed to reprogram the
immune system toward better self-regulation will require
biomarkers for monitoring rejection, tolerance, and unde-
sired toxicity. These will in time provide surrogate mea-
sures of effi cacy, so as to bypass the need for protracted
clinical trials. Simplicity and clinical utility dictate that
such diagnostic aids should be aimed at readily available
tissue biopsies and body fl uids. 128
The momentum for harnessing tolerance processes is
now unstoppable. At this stage, we really do not know how
far we can go on the route to reprogramming the immune
system. At some point, we will need to take stock and
decide whether the patient’s interests can best be served
by maintaining them on a safe dose of drugs; or whether we
aim for complete tolerance with the possibility that some
stochastic event may disturb that process and so jeopar-
dize the transplanted organ. Perhaps the compromise will
be that of aiming for tolerance by weaning patients off
their minimal drug regimens.
Reconstructive transplantation has introduced excit-
ing new possibilities with procedures that offer new hope
that was not available to patients just a few years ago. The
important goals of reconstructive transplantation are to
promote patient and public education; increase awareness
of these procedures as treatment options with quality of
life restoration as justifi cation; and education of referring
physicians, case managers, and patient advocacy groups
and coalition with professional societies. Current tech-
nology is clearly suffi cient to allow for successful trans-
plantation and maintenance of these complex grafts, but
controversy continues over the ethics of these procedures.
Potentially endangering the life of a patient with immu-
nosuppression in order to maintain what is often referred
to as a quality of life graft continues to provoke debate.
Advancements in immunosuppressive therapy, particu-
larly in the induction of transplant tolerance, will reduce
and possibly eliminate the controversy and open a win-
dow of opportunity for many patients deserving of such
reconstruction.

RECONSTRUCTIVE TRANSPLANTATION: EVOLUTION, EXPERIENCE, EMERGING INSIGHTS • 47
REFERENCES

1. Shores JT, Brandacher G, Schneeberger S, et al. Compos-
ite tissue allotransplantation: hand transplantation and
beyond. J Am Acad Orthop Surg . 2010;18(3):127–131.

2. Petruzzo P, Lanzetta M, Dubernard JM, et al. The interna-
tional registry on hand and composite tissue transplanta-
tion. Transplantation . 2008;86:487–492.

3. Jones JW, Gruber SA, Barker JH, Breidenbach WC.
Successful hand transplantation. One-year follow-up.
Louisville Hand Transplant Team. N Engl J Med . 2000;
343:468–473.

4. Lanzetta M, Nolli R, Borgonovo A, et al. Hand transplanta-
tion: ethics, immunosuppression and indications. J Hand
Surg Br . 2001;26:511–516.

5. Pollard MS. Hand transplantation–risks of immunosup-
pression. J Hand Surg Br . 2001;26:517.

6. Breidenbach WC, Gonzales NR, Kaufman CL, et al. Out-
comes of the fi rst 2 American hand transplants at 8 and 6 years
posttransplant. J Hand Surg Am . 2008;33(7):1039–1047.

7. Petruzzo P, Lanzetta M, Dubernard JM, et al. The Interna-
tional Registry on Hand and Composite Tissue Transplan-
tation. Transplantation . 2010;90(12):1590–1594.

8. Veith I, trans. Huang Ti Nei Ching Su Wen. The Yellow
Emperor’s Classic of Internal Medicine . Baltimore, MD:
Williams & Wilkins Co; 1949.

9. Bhishagratna KC. An English translation of the Sushruta
Samhita, based on original Sanskrit text. Calcutta: 1907.
10. Hoernlé AFR. Studies in the Medicine of Ancient India .
Oxford, UK: Clarendon Press; 1907.
11. Hoernlé AFR. Archaelogical Survey of India . Calcutta 22,
1893.
12. Da Varagine J. Leggenda Aurea. Florence, Italy: Libreria
Editrice Fiorentina 648; 1952.
13. Kahan BD. Cosmas and Damian revisited. Transplant Proc.
1983;15(4 suppl1-2):2211–2216.
14. Danilevicius Z. Cosmas and Damian: The patron saints of
medicine in art. JAMA . 1967;201:1021–1025.
15. E Rinaldi. The fi rst homoplastic limb transplant accord-
ing to the legend of saint Cosmas and saint Damian. Ital J
Orthop Traumatol . 1987;13(3):393–406.
16. Converse JM, Casson PR. The historical background of
transplantation. In: Rapaport FT, Dausset J, eds. Human
Transplantation . New York: Grune & Stratton; 1968.
17. Tagliacozzi G. De curtorum chirurgia per insitionem . Venice,
Italy. University of Milan Library, 1597.
18. Tagliacozzi G. De curtorum chirurgia , Lib. I, Reiner G (ed.).
Berloni: Chaps 12,18 (and passim), 1831.
19. Gnudi M. The sympathetic slave. In: The life and times
of Gaspare Tagliacozzi . Los Angeles, CA: Zeitlin and Ver
Brugge; 1976:285–286.
20. Carrel A. La technique operatoire des anastomoses vas-
culaires et la transplantation des visceres. Lyon Med .
1902;99:859.
21. Carrel A. The surgery of blood vessels. Bull Johns Hopkins
Hosp . 1907;18:18.
22. Carrel A. Results of the transplantation of blood vessels,
organs and limbs. JAMA . 1908;51:1662.
23. Landsteiner K. Cell antigens and individual specifi city.
J Immunol . 1928;15:589–600.
24. Flye MW. History of transplantation. In: Flye MW, ed.
Principles of Organ Transplantation . Philadelphia, PA: WB
Saunders Co; 1989.
25. Padgett EC. The full-thickness skin graft in the correction
of soft tissue deformities. JAMA . 1932;98:18.
26. Brown JB. Homografting of skin: with report of success in
identical twins. Surgery . 1937;1:558.
27. Gorer PA, Schütze H. Genetical studies on immunity in
mice: II. Correlation between antibody formation and
resistance. J Hyg (Lond) . 1938;38(6):647–662.
28. Medawar PB. The behavior and fate of skin autografts and
skin homografts in rabbits. J Anat . 1944;78:176.
29. Hall RH. Whole upper extremity transplant for human
being: General plans of procedure and operative technique.
Ann Surg. 1944;120:12.
30. Gibson T, Medawar PB. The fate of skin homografts in man.
J Anat . 1943;77:299.
31. Dausset J. Iso-leuco-anticorps. Acta Haematol . 1958;20:
156–166.
32. Simonson M, Buemann J, Gammeltaft A. Biological incom-
patibility in kidney transplantation in dogs. I. Experimen-
tal and morphological investigations. Acta Pathol Microbiol
Scand . 1953;32:1–35.
33. Mitchison NA. Graft rejection, the histocompatibility
complex and the Langerhans’ cell. Clin Exp Dermatol.
1979;4(4):489–493.
34. Medawar P. A second study of the behavior and fate of
skin homografts in rabbits. (A report to the War Wounds
Committee of the Medical Research Council). J Anat .
1945;69:157–176.
35. Harrison JH, Merrill JP, Murray JE. Renal homotransplan-
tation in identical twins. Surg Forum . 1955;6:432–436.
36. Merrill JP, Murray JE, Harrison JH, Guild WR. Successful
homotransplantation of the human kidney between identi-
cal twins. JAMA. 1956;160(4):277–282.
37. Merrill JP, Murray JE, Harrison JH, et al. Successful
homotransplantation of the kidney between non-identical
twins. N Engl J Med . 1960;262:1251–1260.
38. Murray JE, Merrill JP, Dammin GJ, et al. Kidney trans-
plantation in modifi ed recipients. Ann Surg . 1962;156:
337–355.
39. Murray JE, Merrill JP, Harrison JH, et al. Prolonged sur-
vival of human-kidney homografts by immunosuppressive
drug therapy. N Engl J Med . 1963;268:1315–1323.
40. Peacock EE Jr. Some problems in fl exor tendon healing,
Surgery. 1959;45:415–423.
41. Peacock EE Jr. Restoration of fi nger fl exion with
homologous composite tissue tendon grafts of the digital
fl exor mechanism in human beings. Trans Bull. 1960;7:
418–421.

48 • CHAPTER 4
42. Terasaki PI, McClelland JD. Microdroplet assay of human
serum cytotoxins. Nature . 1964;204:998–1000.
43. Anonymous. Historic cadaver-to-man hand transplant. Med
World News. March 13, 1964.
44. Anonymous. Helping hand. Time. March 6, 1964.
45. Barnes DW, Ford CE, Ilbery PL, et al. Tissue transplanta-
tion in the radiation chimera. J Cell Physiol Suppl . 1957;50
(suppl 1):123–138.
46. Hamburger J, Vaysse J, Crosnier J, et al. Transplantation of a
kidney between non-monozygotic twins after irradiation of
the receiver: good function at the fourth month. Press Med .
1959;67:1771.
47. Hamburger J, Vaysse J, Crosnier J, et al. Renal homotrans-
plantations in man after radiation of the recipient. Am J
Med . 1962;32:854.
48. Schwartz R, Dameshek W. The effects of 6-mercaptopurine
on homograft reactions. J Clin Invest . 1960;39:952–958.
49. Calne RY. The rejection of renal homografts: inhibition in
dogs by 6-mercaptopurine. Lancet . 1960;1:417–418.
50. Zukoski CF, Lee HM, Hume DM. The prolongation
of functional survival of canine renal homografts by
6- mercaptopurine. Surg Forum . 1960;11:470–472.
51. Hitchings GH. Chemotherapy and comparative biochem-
istry: G. H. A. Clowes memorial lecture [review]. Cancer
Res . 1969;29(11):1895–903.
52. Murray JE, Merrill JP, Harrison JH, et al. Prolonged sur-
vival of human-kidney homografts by immunosuppressive
drug therapy. N Engl J Med . 1963;268:1315.
53. Calne RY. The initial study of the immunosuppressive
effects of 6-mercaptopurine and azathioprine in organ
transplantation and a few words on cyclosporin A. World J
Surg . 1982;6(5):637–640.
54. Gorantla VS, Barker JH, Jones JW Jr, et al. Immuno-
suppressive agents in transplantation: mechanisms of
action and current anti-rejection strategies. Microsurgery .
2000;20(8):420.
55. Dreyfuss M, Harri E, Hofmann H, et al. Cyclosporin A and
C; new metabolites from Trichoderma polysporum. Rifai.
Eur J Appl Microbiol. 1976;3:125.
56. Borel JF, Feurer C, Gubler HU, et al. Biological effects
of cyclosporine A; a new antilymphocyte agent. Agents
Actions . 1976;6:468.
57. Calne RY, White DJG, Thiru S, et al. Cyclosporine A in
patients receiving renal allografts from cadaver donors.
Lancet . 1978;2:1323.
58. Goto T, Kino T, Hatanaka H, et al. Discovery of FK-506,
a novel immunosuppressant isolated from Streptomyces
tsukubaensis. Transplant Proc. 1987;19:4.
59. Starzl TE, Todo S, Fung JJ, et al. FK 506 for human liver,
kidney and pancreas transplantation. Lancet. 1989;2:1000.
60. Fung JJ, Todo S, Jain A, et al. Conversion of liver allograft
recipients with cyclosporine related complications from
cyclosporine to FK 506. Transplant Proc . 1990;22:6.
61. Armitage JM, Kormos RL, Griffi th BP, et al. The clini-
cal trial of FK 506 as primary and rescue immunosup-
pression in cardiac transplantation. Transplant Proc .
1991;23:1149.
62. Todo S, Fung JJ, Starzl TE, et al. Liver, kidney and tho-
racic organ transplantation under FK 506. Ann Surg .
1990;212:295.
63. Starzl TE, Fung JJ, Jordan M, et al. Kidney transplantation
under FK 506. JAMA . 1990;264:63.
64. Starzl TE, Abu Elmagd K, Tzakis A, et al. Selected topics
on FK 506: With special reference to rescue extrahepatic
whole organ grafts, transplantation of “forbidden organs,”
side effects, mechanisms, and practical pharmacokinetics.
Transplant Proc. 1991;23:914.
65. Todo S, Tzakis AG, Abou Elmagd K, et al. Intestinal trans-
plantation in composite visceral grafts or alone. Ann Surg .
1992;216:223.
66. Todo S, Tzakis AG, Abou Elmagd K, et al. Cadaveric small
bowel and small bowel-liver transplantation in humans.
Transplantation . 1992;53:369.
67. Allison AC, Eugui EM. Immunosuppressive and other
effects of mycophenolic acid and an ester prodrug, myco-
phenolate mofetil. Immunol Rev . 1993;136:5.
68. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22989),
a new anti-fungal antibiotic: Taxonomy of the producing
streptomycete and isolation of the active principle. J Anti-
biot (Tokyo) . 1975;28:721.
69. Halloran P, Mathew T, Tomlanovich S, et al. Mycopheno-
late mofetil in renal allograft recipients: a pooled effi cacy
analysis of three randomized, double blind clinical studies
in prevention of rejection. The International Mycopheno-
late Mofetil Renal Transplant Study Groups. Transplanta-
tion . 1997;63:39.
70. McAlister VC, Gao Z, Peltekian K, et al. Sirolimus-
tacrolimus combination immunosuppression. Lancet.
2000;355:376.
71. Kahan BD, Podbielski J, Napoli KL, et al. Immunosuppres-
sive effects and safety of sirolimus/cyclosporine combina-
tion regimen for renal transplantation. Transplantation .
1998;66:1040.
72. Shapiro JAM, Lakey JRT, Ryan EA, et al. Islet transplanta-
tion in seven patients with type-1 diabetes mellitus using a
glucocorticoid free immunosuppressive regimen. N Engl J
Med. 2000;343:230.
73. Burnet FM. The new approach to immunology. N Engl J
Med. 1961;264:24.
74. Murray JE. Nobel Prize lecture: the fi rst successful
transplants in man.
transplant/html/murray.
75. Gorantla V, Maldonado C, Frank J, Barker JH. Composite
tissue allotransplantation (CTA): current status and future
insights. Eur J Trauma . 2001;27(6):267-274.
76. Lee WP, Yaremchuk MJ, Pan YC, et al. Relative antigenicity
of components of a vascularized limb allograft. Plast Reconstr
Surg . 1991;87(3):401–411.
77. Bos JD. The skin as an organ of immunity. Clin Exp Immu-
nol . 1997;107(suppl 1):3–5.
78. Swann G. The skin is the body’s largest organ. J Vis Com-
mun Med . 2010;33(4):148–149.
79. Jensen JM, Proksch E. The skin’s barrier. Ital Dermatol
Venereol . 2009;144(6):689–700.

RECONSTRUCTIVE TRANSPLANTATION: EVOLUTION, EXPERIENCE, EMERGING INSIGHTS • 49
80. Bos JD, Luiten RM. Skin immune system. Cancer Treat Res .
2009;146:45–62.
81. Bos JD, Zonneveld I, Das PK, et al. The skin immune sys-
tem (SIS): distribution and immunophenotype of lympho-
cyte subpopulations in normal human skin. J Invest Dermatol .
1987;88(5):569–573.
82. Steinman RM. The dendritic cell system and its role in
immunogenicity. Annu Rev Immunol . 1991;9:271–296.
83. Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin
immune sentinels in health and disease. Nat Rev Immunol .
2009;9(10):679–691.
84. Roediger B, Ng LG, Smith AL, et al. Visualizing den-
dritic cell migration within the skin. Histochem Cell Biol .
2008;130(6):1131–1146.
85. Aoki T, Fujinami T. Demonstration of tissue-specifi c solu-
ble antigens in human skin by immunodiffusion. J Immu-
nol . 1967;98(1):39–45.
86. Steinmuller D, Wakely E, Landas SK. Evidence that epider-
mal alloantigen Epa-1 is an immunogen for murine heart as
well as skin allograft rejection. Transplantation . 1991;51(2):
459–463.
87. Fuchimoto Y, Gleit ZL, Huang CA, et al. Skin-specifi c
alloantigens in miniature swine. Transplantation . 2001;
72(1):122–126.
88. Kanitakis J, Jullien D, Petruzzo P, et al. Clinicopathologic
features of graft rejection of the fi rst human hand allograft.
Transplantation . 2003;76(4):688–693.
89. Cendales LC, Kirk AD, Moresi JM, et al. Composite tis-
sue allotransplantation: classifi cation of clinical acute skin
rejection. Transplantation . 2006;81(3):418–422.
90. Mathes DW, Randolph MA, Solari MG, et al. Split tol-
erance to a composite tissue allograft in a swine model.
Transplantation . 2003;75(1):25–31.
91. Brandacher G, Gorantla VS, Lee WP. Hand allotransplanta-
tion. Semin Plast Surg . 2010;24(1):11–17.
92. Deeg HJ, Storb R. Graft-versus-host disease: pathophysio-
logical and clinical aspects. Annu Rev Med . 1984;35:11–24.
93. Zhang Y, Ruiz P. Solid organ transplant-associated acute
graft-versus-host disease. Arch Pathol Lab Med . 2010;134(8):
1220–1224.
94. Sims KD, Blumberg EA. Common infections in the
lung transplant recipient. Clin Chest Med . 2011;32(2):
327–341.
95. Mao Q, Li YS, Li JS. The current status of multivisceral
transplantation. Hepatobiliary Pancreat Dis Int . 2009;8(4):
345–350.
96. Amirlak B, Gonzalez R, Gorantla V, et al. Creating a hand
transplant program. Clin Plast Surg . 2007;34(2):279–289.
97. Gordon CR, Siemionow M. Requirements for the develop-
ment of a hand transplantation program. Ann Plast Surg .
2009;63(3):262–273.
98. Hollenbeck ST, Erdmann D, Levin LS. Current indications
for hand and face allotransplantation. Transplant Proc .
2009;41(2):495–498.
99. Kvernmo HD, Gorantla VS, Gonzalez RN, Breidenbach
WC 3rd. Hand transplantation. A future clinical option?
Acta Orthop . 2005;76(1):14–27.
100. Younes BS, McDiarmid SV, Martin MG, et al. The effect
of immunosuppression on posttransplant lymphopro-
liferative disease in pediatric liver transplant patients.
Transplantation . 2000;70(1):94.
101. Klapheke M, Marcell C, Taliaferro G, Creamer B. Psychi-
atric assessment of candidates for hand transplantation.
Microsurgery . 2000;20:453.
102. Kanitakis J, Jullien D, Petruzzo P, et al. Immunohistologic
studies of the skin of human hand allografts: Our experi-
ence with two patients. Transplant Proc . 2001;33:1722.
103. Schneeberger S, Gorantla VS, van Riet RP, et al. Atypical
acute rejection after hand transplantation. Am J Transplant .
2008;8(3):688–696.
104. Cendales LC, Kanitakis J, Schneeberger S, et al. The Banff
2007 working classifi cation of skin-containing composite
tissue allograft pathology. Am J Transplan t. 2008;8(7):
1396–1400.
105. Cendales LC, Kirk AD, Moresi JM, et al. Composite tis-
sue allotransplantation: classifi cation of clinical acute skin
rejection [Erratum in: Transplantation . 2006;81(3):422.].
Transplantation . 2006;81(3):418–422.
106. Zeevi A. Immunomonitoring after human limb allotrans-
plantation. Transplant Proc . 1998;30:2711.
107. Ting A, Terasaki PI. Lymphocyte-dependent antibody
cross-matching for transplant patients. Lancet . 1975;1:
304–306.
108. Kanitakis J, Jullien D, Petruzzo P, et al. Clinicopathologic
features of graft rejection of the fi rst human hand allograft.
Transplantation . 2003;76(4):688–693.
109. Pei G.Long term follow up of hand allografts. J Reconst
Microsurg . 2004;1(21):Part II.
110. Kaufman C. Vasculopathy in vascularized composite
allotransplantation. Presented at: the 10th IHCTAS Meet-
ing; April 7-10; Atlanta, Georgia.
111. Demetris AJ, Murase N, Lee RG, et al. Chronic rejection.
A general overview of histopathology and pathophysiology
with emphasis on liver, heart and intestinal allografts. Ann
Transplant . 1997;2(2):27–44.
112. Rubin RH. Impact of cytomegalovirus infection on organ
transplant recipients. Rev Infect Dis . 1990;12(S7):S754.
113. Rubin R. Infection in organ transplant recipients. In: Rubin
RH, Young LS, eds. Clinical Approach to Infection in the
Compromised Host . 3rd ed. New York and London: Plenum
Medical Book Company; 1994:629.
114. Matas A. Chronic rejection in renal transplant recipients–
risk factors and correlates. Clin Transpl . 1994;8(3):332.
115. Michaels PJ, Fishbein MC, Colvin RB. Humoral rejection
of human organ transplants. Springer Semin Immunopathol .
2003;25(2):119.
116. Junge G, Tullius SG, Klitzing V. The infl uence of late acute
rejection episodes on long-term graft outcome after liver
transplantation. Transplant Proc . 2005;37(4):1716.
117. Baines LS, Joseph JT, Jindal RM. Compliance and late
acute rejection after kidney transplantation: a psychomedi-
cal perspective. Clin Transplant . 2002;16:69.
118. Chapman JR. Compliance: the patient, the doctor, and the
medication? Transplantation . 2004;77(5):782.

50 • CHAPTER 4
119. Demetris AJ, Murase N, Starzl TE, Fung JJ. Pathology of
chronic rejection: an overview of common fi ndings and
observations about pathogenic mechanisms and possible
prevention. Graft . 1998;1(2):52–59.
120. Diefenbeck M, Nerlich A, Schneeberger S, et al. Allograft
vasculopathy after allogeneic vascularized knee transplan-
tation. Transpl Int. 2011;24(1):e1–e5.
121. Giraux P, Sirigu A, Schneider F, et al. Cortical reorganiza-
tion in motor cortex after graft of both hands. Nat Neuro-
sci . 2001;4(7):691.
122. Frey SH, Bogdanov S, Smith JC, et al. Chronically deaf-
ferented sensory cortex recovers a grossly typical orga-
nization after allogenic hand transplantation. Curr Biol .
2008;18(19):1530–1534.
123. Billingham RE, Brent L, Medawar PB. Actively acquired
tolerance of foreign cells. 1953. Transplantation . 2003;
76(10):1409–1412.
124. Adams AB, Pearson TC, Larsen CP. Heterologous immu-
nity: an overlooked barrier to tolerance. Immunol Rev .
2003;196:147–160.
125. Calne R, Friend P, Moffatt S, et al. Prope tolerance, periop-
erative campath 1H, and low-dose cyclosporin monother-
apy in renal allograft recipients. Lancet . 1998;351(9117):
1701–1702.
126. Prabhune KA, Gorantla VS, Maldonado C, et al. Mixed
allogeneic chimerism and tolerance to composite tissue
allografts. Microsurgery . 2000;20:441.
127. Calne R, Moffatt SD, Friend PJ, et al. Campath 1H allows
low-dose cyclosporine monotherapy in 31 cadaveric renal
allograft recipients. Transplantation . 1999;68(10):1613.
128. Li B, Hartono C, Ding R, et al. Noninvasive diagnosis of
renal-allograft rejection by measurement of messenger
RNA for perforin and granzyme B in urine. N Engl J Med .
2001;344(13):947–954.

5
c h a p t e r
Negative Pressure
Wound Therapy
Mark B. Schoemann, MD / Christopher Lentz, MD, FACS, FCCM
HISTORY AND DEVELOPMENT
Negative pressure wound therapy (NPWT) is a relatively
recent development in the history of wound care. This
innovative approach uses a closed system that applies
negative pressure to a wound, thereby promoting forma-
tion of granulation tissue and maintaining a moist, wound-
healing environment. The use of NPWT has rapidly gained
acceptance into the armamentarium of the plastic surgeon,
as a growing body of research has demonstrated its ben-
efi ts and successful outcomes. Multiple animal studies and
clinical trials have not only supported its use in plastic sur-
gery but across other fi elds. Papers on NPWT have been
published in almost all surgical specialty journals, but the
best represented are general surgery, orthopedics, urology,
and trauma.
The concept of using negative pressure to treat surgi-
cal wounds was fi rst described in 1952, although it took
approximately another 50 years before NPWT came into
its own as an accepted wound treatment modality. Raffl ,
in his 1952 article, described the placement of closed suc-
tion drains under postmastectomy skin fl aps. The drains
were connected to continuous negative pressure in order
to maintain fl ap adherence to the abdominal wall and to
remove serous fl uid. Two years later, Silvis et al., applied
these principles of negative pressure to patients who had
undergone radical neck dissections. The authors felt an
external pressure dressing to the neck was ineffective;
therefore, closed suction drains were placed under the dis-
section fl aps and removed in 72 hours. They concluded,
“continuous suction has marked advantages over pressure
dressings.”
Forty years later, Nakayama and Soeda described the
use of a negative pressure dressing to affi x a split-thickness
skin graft to the dorsum of the hand. A fi ne silastic mesh
was placed over the skin graft, on top of which a closed
suction drain and two clear adhesive drapes were placed to
seal the system. The authors concluded that their “vacuum
package” dressing was superior to a conventional bolster
dressing over a skin graft because it provided constant uni-
form pressure over an uneven wound surface.
Throughout the 1990s, development of a negative pres-
sure dressing system gained momentum as plastic surgeons
pioneered the next great advancement in wound care.
Argenta and Morykwas from the Bowman Gray School of
Medicine of Wake Forest University in North Carolina pio-
neered the development of a universal negative pressure
dressing system through extensive basic science research
and numerous clinical trials. In 1995, the FDA approved
the marketing of the Vacuum Assisted Closure (V.A.C.)
device in the United States. As a large body of research
accumulated showing the effi cacy of the V.A.C., the FDA
expanded its clinical indications in 2000.
SCIENCE AND PHYSIOLOGY
Many studies have elucidated the basic science principles
that make NPWT an effective modality for treatment of
acute and chronic wounds. The studies were performed
using the V.A.C. device, the only commercially available
NPWT system, and showed it to stimulate wound heal-
ing by several physiologic mechanisms. NPWT improves
wound healing by maintaining a moist environment,
removing edema fl uid, decreasing bacterial colonization,
and augmenting local blood fl ow. 1 On the cellular level,
subatmospheric pressures cause deformation of indi-
vidual cells, which promotes proliferation in the wound

52 • CHAPTER 5
microenvironment. Ultimately, blood fl ow levels are aug-
mented with the use of subatmospheric pressure leading to
increased granulation tissue and improved wound healing.
Animal studies in swine have shown that blood fl ow
increases fourfold in wounds with the use of negative pres-
sure dressings. These studies were performed with laser
Doppler fl ow needle probes placed into the subcutaneous
tissue of wounds covered with a NPWT dressing. A peak
blood fl ow of four times baseline was seen with subatmo-
spheric pressures of 125 mm Hg. Increasing the amount
of negative pressure to values greater than 400 mm Hg,
however, did not enhance but rather decreased blood fl ow.
Local blood fl ow also declined to baseline when subatmo-
spheric pressure was turned off for 5 to 7 minutes. It is
believed that the application of continuous negative pres-
sure to a wound removes suffi cient interstitial edema to
decompress small blood vessels and increase local fl ow.
In addition to increasing local blood fl ow, NPWT has
been shown to increase the rate of granulation tissue for-
mation in a healing wound. The V.A.C. dressing and saline
moistened gauze were placed in wounds on the backs of
swine and compared. Subatmospheric pressure applied
continuously at 125 mm Hg resulted in a 63% increase
in granulation tissue volume when compared with saline
gauze dressing. Mechanical forces that are applied to cells
cause them to proliferate and divide. Plastic surgeons
have long used tissue expanders and the Ilizarov tech-
nique to exploit this property of cells. Subatmospheric
pressures exert micromechanical forces to the exterior
of the cell, which are then transmitted to the intracel-
lular cytoskeleton causing the release of intracellular sec-
ond messengers that promote cellular proliferation. The
V.A.C. device can exert tissue strain from approximately
5% to 20%, which is the range of stretch necessary to
induce cellular proliferation and increase formation of
granulation tissue. The pores of the NPWT foam, which
range in size from 400 to 600 mm, draw up tissue from
the superfi cial surface of the wound and are responsible
for exerting cellular stretch and microdeformation, lead-
ing to cellular proliferation. 2
Infection of a wound with signifi cant number of bacte-
ria (.10 5 organisms/gram tissue) severely interferes with
the normal wound healing process. Application of subat-
mospheric pressure to a wound with a clinically signifi cant
number of bacteria improves clearance. Initial animal stud-
ies examining pig wounds inoculated with 10 8 organisms of
either Staphylococcus aureus or Staphylococcus epidermidis
had decreased bacterial counts after application of NPWT.
By day 4, there was a statistically signifi cant drop in bac-
terial counts to less than 10 5 in the group treated with
NPWT vs wounds not treated with NPWT. Wongworawat
et al. showed that application of NPWT using the V.A.C.
in wounds with positive cultures was extremely effective.
They noted an average reduction of 43% in wound size
at 10 days in patients with culture- positive abscesses that
were debrided, irrigated, and treated with NPWT. However,
one study that quantifi ed bacterial loads in wounds treated
with saline moist gauze and NPWT found no major differ-
ence between treatment arms. While overall bacterial load
was similar in the saline moist gauze and NPWT treatment
groups, NPWT was shown to signifi cantly decrease non-
fermenting gram-negative bacilli ( P ,0.05) and increase
S aureus ( P ,0.05).
PATIENT EVALUATION AND SELECTION
In 1995, the FDA approved the fi rst NPWT device known
as the V.A.C. for the general treatment of nonhealing
chronic wounds. The indications for V.A.C. use were later
expanded in 2000 to include acute, traumatic, and dehisced
wounds in addition to ulcers of the diabetic and pressure
variety. Indications at this time now include treatment of
wounds containing fl aps and grafts. Use of NPWT in each
of these clinical situations is discussed later in the chapter.
Contraindications to use of NPWT are presence of
malignancy in the wound, untreated osteomyelitis, non-
enteric and unexplored fi stulas, and presence of necrotic
tissue with eschar. Although mechanical stretch causes
proliferation of normal cells, its effect on malignant cells
that already have a propensity to proliferate is unknown.
Therefore NPWT is not recommended in a wound with
known malignancy. NPWT can be placed in wounds that
are the result of an oncologic resection, provided that all
gross tumor is removed. NPWT should not be used in
wounds with active osteomyelitis. Osteomyelitis requires
debridement of devitalized tissue and appropriate sys-
temic antibiotic treatment prior to initiation of NPWT.
Use of NPWT on devitalized or necrotic tissue in general
will be futile as the NPWT can only enhance wound heal-
ing of viable tissue. Additionally, application of the poly-
urethane sponge used in NPWT directly over exposed
vessels is contraindicated, as there is the possibility that
subatmospheric pressure might compromise vessel wall
integrity. It is imperative to place fascia or tissue as a
protective layer over vessels if NPWT is to be placed in
close proximity. However, there have been several case
reports of V.A.C. placement directly over exposed femo-
ral bypass grafts for the treatment of groin infections after
lower extremity vascular bypass surgery. A nonadherent
dressing was interposed between the V.A.C. sponge and
the exposed vessels; no complications were reported with
this approach.
Although the use of anticoagulation is not a contrain-
dication to application of a V.A.C. dressing, precaution
should be used in these situations. Exsanguination of an
anticoagulated patient from a V.A.C. dressing is not possi-
ble. The V.A.C. canister, which is typically 250 to 500 mL,
will turn off when completely full, alarming patient care
staff; or, alternatively, the tubing will become occluded with
coagulated blood fi rst. There have been several reports that
NPWT in fully anticoagulated patients can lead to com-
plications, mainly occlusion of the suction tubing with
coagulated blood, which renders the treatment ineffective.
In these cases, discontinuation of NPWT is recommended

NEGATIVE PRESSURE WOUND THERAPY • 53
and institution of a more conventional mode of wound
dressing be utilized.
PATIENT PREPARATION
The fi rst step to ensure successful outcomes with NPWT
is to prepare the wound bed for application of a subat-
mospheric dressing. Devitalized and necrotic tissue must
be debrided adequately from the wound. As mentioned
earlier, NPWT is only able to augment the healing of via-
ble tissue, therefore, any necrotic tissue must be removed
before placement of the foam. Irrigation of the wound with
normal saline or a pulse irrigator with or without antibi-
otic solution may be required in contaminated wounds.
Achieving adequate hemostasis is imperative, as removal
of copious amounts of blood from the wound can lead to
occlusion of the suction tubing.
Once the wound has been adequately debrided and
adequate hemostasis achieved, the NPWT foam dressing
is then placed into the wound. Three types of foam dress-
ing are currently marketed to be used with the V.A.C. sys-
tem: a black polyurethane foam, a white polyvinyl alcohol
foam, and a silver impregnated foam dressing. The black
polyurethane foam dressing (pore size 400–600 mm) is the
traditional foam dressing that can be used in a variety of
wounds. The smaller pore size of the newer polyvinyl alco-
hol foam (pore size 60–270 mm) is designed to prevent
the ingrowth of granulation tissue into the foam, which
is benefi cial when dressing skin grafts and painful wounds
with NPWT. Placement of a layer of nonadherent gauze,
such as Xeroform or Adaptic, which is readily available in
the operating room, between a skin graft and the black
polyurethane foam can prevent ingrowth of granulation
tissue. GranuFoam Silver, the most recently introduced
foam dressing, is impregnated with silver, which provides
a continuous release of antimicrobial silver ions that inter-
fere with the electron transport chain of a wide spectrum
of bacteria. Randomized trials comparing the bacterial
clearance of the silver impregnated foam to the traditional
black polyurethane foam have not yet been performed.
Following the appropriate selection of the foam dressing,
it must be cut to suitable dimensions for placement in the
wound. Heavy mayo scissors are adequate in the operating
room to cut through the 1-inch thick foam. When plac-
ing a NPWT foam dressing in a superfi cial wound of large
surface area, we recommend cutting the 1-inch thick foam
dressing into two, half-inch thick, pieces. The foam dressing
should cover the entire wound base, sides, and undermined
areas and should fi t easily into the wound without the need
for packing it forcibly. The foam should not be placed in
direct contact with native epidermis at the edges of the
wound. Multiple pieces of foam should be in direct con-
tact, so that subatmospheric pressure is distributed evenly
throughout the wound. A surgical stapler can be used to
keep multiple pieces of foam in continuity. Placing a foam
dressing in a wound with irregular contour can be diffi cult.
In wounds encompassing the partial circumference of the
leg or arm, we secure the foam dressing in place with ves-
sel loops. The vessel loops are secured to the edges of the
wound with a stapler and then crisscrossed over the foam
and then eventually tied down ( Figure 5-1 ). This allows
manipulation of the extremity while placing the occlusive
drape without dislodgement of the foam.
After the foam dressing has been appropriately sized
and placed into the wound, the occlusive dressing is then
applied. For the occlusive dressing to maintain adequate
seal, the periwound area must be clean and dry. Generous
application of Mastisol, Tincture of Benzoin, or Cavilon No
Sting Barrier Film to the periwound skin is recommended.
Once the skin preparation has had time to adequately dry,
the occlusive dressing is placed over the foam dressing
with a 3 to 5 cm border of overlap around the wound. The
wound drape comes supplied in 25 cm 3 35 cm sheets
in the package. We have found that trying to place such
large sheets over irregularly shaped wounds and joints to
be cumbersome. Cutting the occlusive wound drapes into
approximately 10 cm wide strips allows easier application;
however, each strip should overlap the previous one by
approximately 2 cm ( Figure 5-2A ). More complex wounds
with irregular contours, such as those encountered in the
groin and across joints, should be dressed with even thinner
strips of the occlusive dressing ( Figure 5-2B ). Wounds with
copious effl uent can also pose problems of maintaining
adequate periwound seal with the occlusive dressing. Often
times, wound effl uent will pool in the dependent portion of
the wound. The occlusive drape should be applied here last.
FIGURE 5-1. Placing the NPWT foam dressing in
wounds with irregular contour or convex shape can be
problematic. To secure the foam dressing, vessel loops are
secured at the edges of the wound with a stapler and then
interlaced over the top of it. The surgeon is then able to apply
the occlusive dressing with both hands unconstrained.

54 • CHAPTER 5
With the nondependant portions dressed fi rst, the suction
tubing can be attached and connected to standard operat-
ing room suction tubing. This maneuver will reduce wound
effl uent and pooling in the dependent portion, allowing
placement of the occlusive drape to a drier area.
With the foam placed into the wound and occlu-
sive dressing applied, the last step to successful NPWT
is placement of suction tubing. Older V.A.C. units came
with a noncollapsible suction tubing that was to be placed
into the foam dressing directly and then covered with
occlusive dressing. Suction tubing could not be placed
over bony prominences or weight bearing areas, as there
was the possibility of soft tissue breakdown. Newer V.A.C.
devices come with a noncollapsible suction tubing ter-
minating with a circle of self-contained occlusive drape
called the TRAC pad. A small, 1 cm cut is made through
the occlusive dressing that is covering the foam and the
TRAC pad is simply placed over it. Either type of tubing is
then connected to a V.A.C. device and the desired amount
of subatmospheric pressure established. When NPWT is
applied to two different anatomic sites, a Y connector can
be used to connect two pieces of suction tubing to one
V.A.C. device. If two sites are in close proximity, a bridge
can be formed to extend the subatmospheric pressure
from the primary NPWT site to a nearby secondary site.
This can be accomplished by placing a section of arterial
line tubing or nasogastric suction tubing, both of which
are non-compressible, between the sites and covering with
occlusive dressing ( Figure 5-3 ). Alternatively, a bridge can
be formed by placing a piece of NPWT foam between
two sites provided the native skin underneath the bridge
is protected with either Xeroform gauze or DuoDERM
( Figure 5-4 ).
Two of the most common problems encountered with
NPWT are the presence of an air leak from the occlusive
wound drape and occlusion of the suction tubing. When
the V.A.C. device alarms that an air leak has been detected,
it is crucial to handle this problem in a timely manner. An
inadequate seal will result in loss of a moist wound envi-
ronment and potential wound desiccation on account of
a continuous air current over the wound surface. The fi rst
maneuver is to check the suction tubing and ensure that
it has not been disconnected from the V.A.C. device or
is kinked. If the tubing appears to be intact, then the
leak is likely from disruption of the periwound occlusive
dressing. An additional piece of occlusive wound drape
can be placed over the initial dressing in order to obtain
adequate sealing. The occlusive drape supplied with the
V.A.C. device should be used, as Tegaderm or Opsite are
porous and will not be able to sustain an adequate seal at

FIGURE 5-2. (A) Application of the occlusive dressing is made easier by cutting it
lengthwise into approximately 10 cm wide strips. (B) Wounds with more irregular contour
require thinner strips of occlusive dressing. Subsequent strips should be laid down with
3 to 4 cm of overlap.
A
B

Nasogastric
Tube
FIGURE 5-3. Two wounds in proximity that have been
treated with NPWT can be connected with noncompressible
tubing, such as arterial line tubing or in this case a nasogastric
tube.

NEGATIVE PRESSURE WOUND THERAPY • 55
subatmospheric pressures. If placement of multiple pieces
of occlusive dressing does not solve the problem, then the
initial occlusive dressing should be taken down and a new
one applied with thorough skin prep. Occlusion of the suc-
tion tubing can occur commonly in wounds that produce a
thick effl uent. Placement of a new piece of suction tubing
onto the foam dressing will remedy this problem.
TECHNIQUES
Perioperative Use of Negative
Pressure Dressings on Skin Grafts
Skin grafting with full-thickness and partial-thickness
grafts is an integral tool in the plastic surgeon’s recon-
structive armamentarium. In order for a skin graft to
survive, it must have suffi cient contact with the recipi-
ent bed and shear forces minimized. A bolster dressing,
consisting of cotton fl uff secured with interlacing sutures,
is commonly used to accomplish this. In small, fl at, well-
granulated beds with minimal motion, these types of
dressings are adequate. However, in larger recipient beds
subjected to excessive shear force, graft survival can be
severely compromised. Recognizing that bolster dress-
ings apply variable pressure and can conceal a developing
hematoma, Nakayama et al., were the fi rst to describe the
use of NPWT to secure split-thickness skin grafts in 1990.
They noted NPWT to be superior to conventional bolster
and pressure bandages. NPWT provides constant uniform
pressure over the entire area of the skin graft, as well as on
irregular surfaces and recipient beds subjected to exces-
sive motion ( Figure 5-5 ).
As the use of the V.A.C. became more widespread
in the 1990s and its indication were broadened, use of
NPWT as a perioperative dressing for skin grafts, instead of
the traditional bolster dressing, became more widespread.
Early case reports in the literature described successful
skin grafting with NPWT in even the most diffi cult ana-
tomic locations, including the perineum and axilla. Soon
after, Schneider, Morykwas, and Argenta reported using
the V.A.C. to secure split-thickness skin graft to recipi-
ent beds in over 100 patients. 3 They noted complete graft
take in all but two patients who incidentally had chronic
wounds that were grossly contaminated. A retrospective

FIGURE 5-4. (A) A young man presents with partial-thickness injuries of the hand
after grabbing a hot metal pipe. His wounds have been debrided and prepared for NPWT
application. (B) DuoDERM is placed around both wounds in order to protect the native
epidermis and to allow the placement of one large foam dressing instead of two smaller
foam dressings. (C) Large foam dressing is placed over DuoDERM and both wounds.
(D) NPWT applied to both wounds simultaneously.
A
C
B
D

56 • CHAPTER 5
review of 61 patients requiring split-thickness skin grafts
for acute traumatic and thermal injury burns demon-
strated that the V.A.C. was superior to bolster dressings.
Patients receiving traditional bolster dressings had less
graft take (89%) and required more repeat skin grafts
(19%) when compared to the V.A.C. group which had
a take rate of 96% and required repeat grafting in 3%. 4
With the ability to conform to irregular contours, NPWT
has expanded the possibilities of skin grafting and broad-
ens the plastic surgeon’s ability to place skin grafts in dif-
fi cult locations.
In order to use NPWT as a perioperative skin graft
dressing successfully, one must fi rst adhere to the basic
plastic surgery principles of skin grafting. The recipient
bed must be prepared in the usual manner with adequate
debridement of necrotic and nonviable tissue along with
adequate hemostasis. Once this is achieved, the skin graft
is placed onto the recipient bed and its edges trimmed. We
secure the skin graft to the edge of the wound with sur-
gical staples. A protective layer must be placed between
the skin graft and the polyurethane foam dressing in
order to prevent ingrowth of the skin graft into the foam
and eventual graft disruption when the foam is removed.
Either Xeroform gauze or Adaptic is suffi cient to prevent
ingrowth. With the skin graft and protective layer down,
the foam dressing is cut to size, placed onto the wound,
and covered with the occlusive adhesive dressing. Suction
tubing is connected and set to continuous negative pres-
sure of 125 mm Hg.
The NPWT dressing should be left in place for 5
full days; others have reported securing skin grafts with
NPWT for 3 days. Postoperatively the patient is able to
move around without fear of disrupting the skin graft.
When the NPWT dressing is ready to be removed after 5
days, it must be removed slowly, layer by layer, in order
to avoid unintentionally harming the graft. Removal of
the NPWT dressing can sometimes be painful and pro-
voke feelings of anxiety for the patient and, therefore,
premedication with analgesics in selected patients is rea-
sonable. Staples from the edges of the wound are care-
fully removed. Routine postoperative care of the skin
graft ensues.

FIGURE 5-5. (A) A patient presenting with partial-thickness skin loss after the cuff
of his pants caught on fi re. (B) Skin grafts have been applied after the wound bed was
adequately debrided of nonviable tissue. (C) Ankle after NPWT has been applied. (D) Skin
graft 3 weeks after removal of NPWT.
A
C
B
D

NEGATIVE PRESSURE WOUND THERAPY • 57
Treatment of Pressure
Ulcers and Chronic Wounds
Pressure ulcers result when sustained pressure hinders
blood fl ow to vulnerable areas of the body, mainly the
dependent portions: buttocks, hips, and heels. With local-
ized ischemia, the structural integrity of the soft tis-
sue begins to deteriorate leading to a progression from
partial- thickness skin loss to full-thickness skin loss and
then destruction of underlying subcutaneous fat, fascia,
and bone. These wounds pose a particular challenge to
the plastic surgeon, as healing is often impaired second-
ary to local factors (infection, pressure, and edema) and
by systemic factors (diabetes mellitus, peripheral vascular
disease, and malnutrition). Combined, these factors hinder
the timely and orderly progression of wound healing, ulti-
mately leading to a chronic wound.
Both studies and case reports have confi rmed NPWT as
a useful adjunct in the treatment of these complex and dif-
fi cult wounds. Recently, Isago and colleagues showed that
application of NPWT in 10 patients with pressure ulcers
(fi ve sacral, three trochanteric, and two ischial) penetrating
the deep fascia and involving bone, resulted in a 55% reduc-
tion in wound area and 61% reduction in wound depth.
Wounds were small enough to heal by secondary intention
in three patients, while the other seven required operative
intervention for defi nitive closure. Joseph et al. randomized
24 patients with 36 chronic wounds (79% pressure ulcers)
to receive either saline wet-to-moist dressing changes or
NPWT with the V.A.C. device. Wound volume at 6 weeks
was reduced 78% in the NPWT group vs 30% in the stan-
dard saline dressing group ( P 50.038). Histologically, 64%
of wounds treated with NPWT exhibited granulation
tissue, while 81% of the standard saline dressing group
showed evidence of infl ammation and fi brosis.
The etiology of pressure ulcers is multifactorial and
therefore requires a multidisciplinary approach involving
physicians from plastic surgery, orthopedic surgery, inter-
nal medicine, as well as nutritionists and nurses. Before
the wound is evaluated, local and systemic factors inhibit-
ing wound healing should be identifi ed. The wound is then
examined and classifi ed according to the National Pressure
Ulcer Advisory Panel as stage I, II, III, or IV pressure ulcer.
NPWT is not an appropriate treatment modality for stages I
and II pressure ulcers; however, patients with stages III and
IV may be candidates. If the ulcer is amenable to closure
with a surgical procedure and the patient is a good surgi-
cal candidate, then surgical intervention is recommended.
If the wound can be closed surgically but the medical and
nutritional status of the patient does not permit going to
the operating room, NPWT can be initiated while patient
health status is optimized. The wound should be debri-
ded of necrotic tissue and exudate prior to initiation of
NPWT. With dressing changes every 48 to 72 hours, the
wound is re-evaluated at the end of 2 weeks and surgical
intervention is pursued if the patient’s condition has been
optimized. Otherwise, NPWT is continued for an addi-
tional 2 weeks and the patient re-evaluated for surgery. For
patients with stage III or IV pressure ulcers who will not
be surgical candidates because of medical comorbidities,
NPWT can be initiated as a primary treatment modality
in an attempt to close the wound by secondary intention.
This is providing that there are no patient characteristics
that would make NPWT an unfavorable option, such as
inability to adhere to a treatment protocol of consistently
offl oading pressure, intolerable pain with dressing changes,
and bleeding disorders/platelet dysfunction. Wound char-
acteristics that would make NPWT a poor option in non-
surgical candidates include inadequate vascular supply,
desiccation and fi brosis, and inability to maintain a seal due
to hyperhidrosis and incontinence.
Sternal Wound Infections
Approximately 650,000 open heart operations are per-
formed every year and, although mediastinitis and sternal
wound infections are rare, they harbor signifi cant morbid-
ity and mortality. Pooled data from retrospective studies
has shown the prevalence of mediastinitis and deep sternal
wound infections to be 1.2% with an average mortality of
20%. Plastic surgeons are often consulted to manage and
treat these challenging wounds. There has been an evo-
lution in the treatment of sternal wound infections since
the introduction of the median sternotomy by Julian in
1957. In the past, aggressive debridement followed by
wet-to-dry dressing changes and antibiotic irrigation with
catheters was the norm. Once the wound had contracted
suffi ciently, defi nitive closure could be accomplished with
fl aps. Recently, the use of NPWT has been shown to be
effi cacious as a primary treatment modality, or a bridge to
sternal wound reconstruction.
Initial case reports of using NPWT for sternal wounds
showed it to be a promising technique to eliminate the
need for wet-to-dry dressing changes and bridge the patient
to defi nitive closure. Song and colleagues performed a ret-
rospective review of 35 consecutive patients treated for
sternal wound complications. After surgical debridement,
18 patients were treated with traditional wet-to-dry dress-
ing changes twice a day while 17 patients were treated
with NPWT using the V.A.C. device. In comparison to the
traditional dressing group, the V.A.C. therapy group had
a shorter interval between debridement and fl ap closure
(6.2 days vs 8.5 days), signifi cantly less mean dressing
changes (3 vs 17; P ,0.05), and required less soft tissue
fl aps per patient (0.9 vs 1.5; P ,0.05). Two years later, Song
reported the largest series of patients treated with NPWT
for sternal wound complications. Of the 103 patients who
had NPWT after surgical debridement, 68% eventually
underwent open reduction internal fi xation with and with-
out fl ap closure while 32% had no defi nitive operation. Of
the patients who had no defi nitive closure, 18 patients
died secondary to their disease process, and 15 closed by
secondary intention. The authors therefore concluded that
NPWT could be used as a fi rst-line treatment modality for
sternal wound reconstruction in select patients, avoiding
local fl aps. 5

58 • CHAPTER 5
As with all wounds, adequate debridement of necrotic
soft tissue and bone is essential for successful outcomes
with NPWT. In the operating room, all grossly infected
soft tissue and osteomyelitis should be thoroughly deb-
rided and irrigated. Once debrided, a NPWT foam
dressing is placed into the wound with adequate con-
tact with remaining bone and soft tissue structures in
the wound. In some cases, extensive sternal bone deb-
ridement may leave exposed epicardium. This presents
a particular problem as the porous black polyurethane
foam can become adherent when placed directly over
the heart. Some have reported that petrolatum-coated
gauze or Xeroform gauze placed between the heart and
the NPWT foam results in adherence of the gauze to the
epicardium. Harlan reported good results using a thin
(0.01 inch thick) sheet of silicone placed between the
epicardium and the NPWT foam and reported no adher-
ence problems. The NPWT dressing should be changed
every 24 to 48 hours, depending on the original level of
gross infection. Adequate analgesia should be adminis-
tered with each dressing change. Disconnecting the suc-
tion tubing and instilling sterile saline through the tube
and saturating the foam can loosen it and make dressing
changes less painful. Duration of NPWT is based on clini-
cal judgment. For large chest wounds in which NPWT is
used as a bridge for fl ap reconstruction, there should be
suffi cient granulation tissue and no evidence of necrotic
or infected tissue in the wound. For superfi cial wounds
with localized areas of infection, placement of a NPWT
dressing after debridement may be all that is needed for
closure by secondary intention.
Complex Orthopedic Wounds
Orthopedic wounds with exposed bone, tendon, rods, or
plates present particular reconstructive problems because
these wounds are subject to malunion, infection, and can
be devoid of soft tissue, especially after high-energy trauma.
In the past, plastic surgeons often performed technically
challenging and complex free fl ap coverage of these lower
extremity wounds. NPWT has been tested in the realm of
acute and chronic orthopedic wounds and has proven to
be useful as a bridge to local soft tissue transfer, avoiding
the need for free fl aps, and in select patients, a primary
treatment modality. In large open wounds, NPWT can be
applied after debridement, converting the open wound
to a contained closed wound. With removal of edema
fl uid and an increase in local blood fl ow, these large open
wounds can be stabilized and enriched with healthy granu-
lation tissue in anticipation for soft tissue transfer. Small
areas of exposed bone, tendon, and orthopedic hardware
can be treated with NPWT and then closed primarily or
covered with a split-thickness skin graft, avoiding the need
for complex reconstruction.
Recognizing the positive impact of NPWT in other
types of wounds, DeFranzo and Argenta investigated
the effi cacy of using the V.A.C. device in orthopedic
wounds. 6 Their series consisted of 75 patients, of which
49 had orthopedic wounds secondary to acute trauma
and 26 had wounds due to postsurgical dehiscence, infec-
tion, or failed fl ap coverage. After adequate operative
debridement, a V.A.C. dressing was applied and changed
every 48 hours. Defi nitive wound closure was achieved
in 95% of the patients, of which 77% were skin grafted,
16% closed primarily, and 6% had reconstruction with
local musculocutaneous or fasciocutaneous fl aps. No
patients enrolled in the study required free fl ap cover-
age. Parrett and colleagues also noted a decreased trend
in free fl ap coverage of open tibia-fi bula fractures when
they retrospectively evaluated 290 consecutive patients
over a 12-year period. The decrease in free fl ap coverage
coincided with the introduction of NPWT technology
and thus free tissue transfer dropped from 42% to 11%
over a 12-year period. Herscovici et al. utilized NPWT on
26 wounds with soft tissue defects that were the result
of high-energy trauma and noted that 57% were closed
primarily or with skin grafts avoiding free tissue transfer.
While the use of NPWT does not eliminate the need for
free tissue transfer, it allows less invasive and complex sur-
gical techniques to be employed for adequate coverage.
In the management of complex orthopedic wounds,
and all other types of wounds treated with NPWT, ini-
tial debridement in the operating room is paramount. All
necrotic soft tissue and nonviable bone must be aggres-
sively debrided for NPWT to be successful. Placing NPWT
over large areas of exposed orthopedic hardware is advis-
able as a temporary measure to better control the wound
and prepare it for muscle coverage or split-thickness skin
graft if granulation tissue is suffi cient. Smaller areas of
exposed hardware can be treated with NPWT and soft
tissue closed primarily after acceptable contraction of
wound skin edges. Independent of wound size, any hard-
ware that is covered with a NPWT dressing must be fi xed
in solid healthy bone. Plate and screw exposure time
should be limited before initiation of NPWT, preferably
less than 72 hours.
Dermal Substitutes
In addition to increasing the rate of skin graft take on
irregularly contoured wounds, NPWT has been shown
to improve incorporation of the dermal template Integra.
Integra is a bilaminar sheet consisting of a collagen/
glycosamine matrix and a protective silicone covering.
In wounds requiring full-thickness coverage, an Integra
sheet is placed onto the wound and secured at the wound
edges, much like a skin graft. After 2 to 4 weeks, the der-
mal template becomes fully integrated into the wound
bed and the protective silicone layer can be removed.
An ultrathin (,0.0005 inch) split-thickness skin graft is
then placed over the neodermis. Use of this technique can
improve the cosmesis and function of a reconstruction and
can avoid full-thickness skin graft donor sites. Placement
of Integra with subsequent split-thickness skin grafting

NEGATIVE PRESSURE WOUND THERAPY • 59
allows full-thickness coverage with only minimal cost to
the patient, using a split-thickness skin graft donor site.
Preliminary studies with Integra reported excellent take
rates of 95% to 100% although other researchers and clini-
cians were not able to reproduce such results, especially in
diffi cult to graft areas. Use of NPWT as a bolster to secure
Integra can decrease incorporation time to approximately
1 week with excellent take rates upward of 95%. Thus, a
two-stage approach consisting of resurfacing with Integra
followed by skin grafting can be reduced from 2 to 4 weeks
to approximately 11 to 12 days. Furthermore, it is reported
that NPWT can facilitate incorporation of Integra over
bone and tendon, which can then be skin grafted, obviat-
ing the need for complex rotational or free fl aps.
Miscellaneous Applications
In addition to the aforementioned applications, NPWT
has been used in a variety of clinical situations by taking
advantage of its ability to maintain a moist wound environ-
ment, increase local blood fl ow, and increase granulation
tissue. There are many case reports in the literature about
new and innovative applications of NPWT.
Full-thickness skin loss of the scalp with exposed bone
due to burns, trauma, and oncologic resections present
a reconstructive challenge to the plastic surgeon. These
wounds were often treated in the past with multiple-
staged procedures with local or free fl aps. Recognizing
the utility of NPWT for securing skin grafts, Molnar and
colleagues reported four cases of successfully skin graft-
ing exposed skull with NPWT in a single operation. The
outer table of the skull was burred down to the diploic
space and split-thickness skin grafts were secured at the
periphery with suture. A V.A.C. device was placed over
the skin graft with an intervening layer of Adaptic and
removed in 4 days. Graft taken using this approach was
99% amongst the four patients. Thus, NPWT is a use-
ful adjunct to treating wounds with exposed skull in a
single operation, averting the need for more complex fl ap
coverage.
Skin defects of the penile shaft that occur with burns,
trauma, necrotizing soft tissue infections, or oncologic resec-
tions, while uncommon, are diffi cult reconstructive prob-
lems. Resurfacing the irregular contour of the male genitalia
with split-thickness skin grafts using conventional bolsters
is problematic because the skin grafts are subjected to
considerable shear forces when the patient moves. Several
case reports in the literature point to NPWT as an ideal
method of securing a split-thickness skin graft for penile
reconstruction. In one case report, NPWT was applied
circumferentially to resurface the penile shaft in three
patients with Fornier gangrene and one patient after onco-
logic resection. NPWT was maintained for 72 hours with
reports of good graft take. Others have reported similar
outcomes but described placing sterile wooden tongue
blades longitudinally in the V.A.C. sponge to maintain the
penis in a linear orientation.
FUTURE DIRECTIONS
Although application of NPWT stimulates a fourfold
increase in blood fl ow in open wound beds, its effect on
closed wounds and intact skin have only recently been elu-
cidated. Timmers et al. applied NPWT to the intact forearm
skin of 10 volunteers and measured cutaneous blood fl ow
with noninvasive laser Doppler probes in response to vary-
ing degrees of negative pressure. At 300 mm Hg of nega-
tive pressure, cutaneous blood fl ow increased 5.6-fold over
baseline with the polyurethane foam dressing ( P 50.009)
and 2.9-fold over baseline with the polyvinyl alcohol foam
dressing ( P 50.063). 7 The clinical signifi cance of these
fi ndings is currently unknown but the concept of increas-
ing cutaneous blood fl ow with NPWT could be benefi cial
in preventing skin loss in myocutaneous fl aps and other
superfi cial wounds with diminished blood supply.
Wound instillation therapy is a recent development in
the evolution of NPWT that allows the delivery of dif-
ferent therapeutic solutions to the wound bed, allowing
the physician to manipulate the wound milieu as deemed
appropriate. The V.A.C. Instill system was designed to
improve wound healing in particularly diffi cult wounds
with chronic or acute infections. It is composed of the
standard V.A.C. dressing along with an additional piece
of tubing to allow for infusion of solutions into the foam
dressing. Subatmospheric pressure is stopped by the V.A.C.
Instill machine, fl uid delivered via the second tube by posi-
tive pressure, and then subatmospheric pressure resumed
after a predetermined length of time. Solutions that can
be instilled include topical cleansers, anesthetics, antibiot-
ics, antiseptics, and antifungals. Research evaluating the
effi cacy of instillation NPWT with the aforementioned
instillation therapies along with enzymatic and proteolytic
agents is continuing. Clinical studies will help uncover
which solutions are best suited for a particular clinical situ-
ation and what the ideal cycling of instillation and NPWT
is. As wound healing research progresses on the molecular
level, it is possible that instillation NPWT will someday
permit the delivery of cytokines and growth factors, allow-
ing the plastic surgeon fundamental control of the wound
healing process.
The advent of NPWT over the past 10 years has trig-
gered a paradigm shift in the way that plastic surgeons
treat wounds. Although initially used for the treatment
for chronic nonhealing wounds, the creativity of surgeons
across all surgical subspecialties has brought about an ever-
expanding list of NPWT applications. NPWT has thus
modifi ed the reconstructive ladder by allowing placement
of skin grafts in previously inhospitable recipient beds,
decreasing the time needed for dermal template incorpo-
ration, and avoiding the use of complex free tissue fl aps. It
is likely that in the ensuing years, the ingenuity of surgeons
will expand the list of indications for NPWT. However, it is
essential that large prospective trials be performed evalu-
ating the effectiveness of these new applications as they
emerge.

60 • CHAPTER 5
REFERENCES
1. Morykwas MJ, Argenta LC, Shelton-Brown EI, McGuirt W.
Vacuum-assisted closure: a new method for wound control
and treatment: animal studies and basic foundation. Ann
Plastic Surg . 1997;38(6):553–562.
2. Saxena V, Hwang CW, Huang S, et al. Vacuum-assisted clo-
sure: microdeformations of wounds and cell proliferation.
Plast Reconstr Surg . 2004;114(5):1086–1096; discussion
1097–1098.
3. Schneider AM, Morykwas MJ, Argenta LC. A new and reli-
able method of securing skin grafts to the diffi cult recipient
bed. Plast Reconstr Surg. 1998;102(4):1195–1198.
4. Scherer LA, Shiver S, Chang M, et al. The vacuum assisted
closure device: a method of securing skin grafts and improv-
ing graft survival. Arch Surg. 2002;137(8):930–933; discus-
sion 933–934.
5. Agarwal JP, Ogilvie M, Wu LC, et al. Vacuum-assisted closure
for sternal wounds: a fi rst-line therapeutic management
approach. Plast Reconstr Surg. 2005;116(4):1035–1040;
discussion 1041–1043.
6. DeFranzo AJ, Argenta LC, Marks MW, et al. The use of
vacuum-assisted closure therapy for the treatment of lower-
extremity wounds with exposed bone. Plast Reconstr Surg.
2001;108(5):1184–1191.
7. Timmers MS, Le Cessie S, Banwell P, Jukema GN. The
effects of varying degrees of pressure delivered by negative-
pressure wound therapy on skin perfusion. Ann Plastic Surg.
2005;55(6):665–671.

Anesthesia for Plastic Surgery
Meredith S. Collins, MD / Sameer Bashey, MD / Laurence M. Hausman, MD
6
c h a p t e r
INTRODUCTION
According to the American Board of Plastic Surgeons,
more than 11 million cosmetic procedures are performed
annually in the United States. 1 With the continued
increase in the number and complexity of plastic surgi-
cal procedures performed each year, careful clinical deci-
sion making for the safe and effective administration of
anesthesia for these patients is imperative. Many plastic
surgical procedures are performed not only in hospitals
and free-standing ambulatory surgery centers but also in
the offi ce-based setting. This shift in surgical venues has
served to reinforce the need to consider all factors imping-
ing on patient safety.
Furthermore, patients are discharged home soon after
the completion of their surgical procedure without an
overnight or extended stay. 2 It is for these reasons that the
anesthetic technique is as vital as the procedure itself. The
technique in which the various anesthetic agents are used
may impact the quality and quantity of recovery time.
Moreover, the anesthetic technique may contribute not
only to patient safety, but also to the overall success of
nearly every cosmetic procedure.
PATIENT EVALUATION AND SELECTION
An anesthetic complication during cosmetic surgery is rare
in part because of the rigorous screening process a patient
undergoes prior to any elective procedure. The patient
should be medically optimized before receiving any type
of anesthetic ranging from local anesthesia alone through
minimal, moderate, or deep sedation and general anesthe-
sia. The American Society of Anesthesiologists (ASA) has
defi ned these depths of sedation along an anesthetic con-
tinuum. 3 In preparing a patient for surgery, it is useful to
use the ASA Physical Status (ASA PS) score to help deter-
mine his or her risk from anesthesia. Within this scoring
system, a patient’s physical condition is classifi ed into one
of six categories: 4
ASA PS I—Completely healthy
ASA PS II—Mild controlled illness or disease with no
interference to patient’s daily life
ASA PS III—Illness or disease of more than two organ
systems
ASA PS IV—Uncontrolled illness or disease, which is a
constant threat to life
ASA PS V—Expected to die within 24 hours with or
without surgery
ASA PS VI—Organ donor
Most would agree that a class I or II patient is a suitable
candidate for an elective, outpatient procedure, while a
class III patient would most likely need additional assess-
ment before being considered suitable for outpatient
procedures and may even be better operated upon in an
inpatient setting. In addition to a thorough history and
physical exam, laboratory screenings are often required.
Commonly ordered tests include hemoglobin and hemat-
ocrit, electrolytes, blood glucose, urinalysis, an EKG, and a
chest x-ray. All laboratory studies should be ordered based
on the patient’s comorbidities. Routine laboratory screen-
ings should be considered a thing of the past. The only
routine screening that should be considered is that any
menstruating woman should have a negative urine preg-
nancy test within 24 hours of the procedure. An EKG for
patients older than 50 years of age may also be a help-
ful screen. A specifi c preoperative visit with an anesthe-
siologist is not routinely required because the primary

62 • CHAPTER 6
care physician should be able to furnish all of the above
information.
PATIENT PREPARATION
All patients should be instructed to abstain from solid
food 8 hours prior to surgery and clear liquids 2 hours
before surgery. The history of this recommendation likely
comes from a report published in 1946 by Mendelson,
who noted a high incidence of pulmonary aspiration in
obstetric patients undergoing general anesthesia. More
recently, the American Society of Anesthesiologists Task
Force on Preoperative Fasting published a concrete recom-
mendation. 5 They require a minimum fasting period for
clear liquids of 2 hours and a minimum of 6 hours for milk
or a light meal. This fasting period should be extended
to 8 hours for patients who have ingested any meal con-
taining fried or fatty foods. Since it is easiest and safest to
adopt a single, preoperative fasting rule prior to elective
surgery, 8 hours is the most appropriate because it covers
all foods and liquids. In most healthy adults undergoing
elective cosmetic surgery the following morning, there is
minimal inconvenience from an overnight fast.
In addition to urging a patient to get plenty of rest the
night before the procedure, the surgeon may consider
prescribing a medication that provides somnolence and a
small degree of anxiolysis. It is common for patients to feel
anxiety and apprehension before surgery. A preoperative
benzodiazepine is a suitable choice because of its ability
to provide both somnolence and anxiolysis. In fact, many
plastic surgeons treat preoperative anxiety prophylacti-
cally. Specifi c benzodiazepines such as alprazolam (Xanax)
or lorazepam (Ativan) can be prescribed to patients 1 to
3 days prior to the procedure in doses of 0.25 to 0.50 mg
three times daily and 2 to 4 mg twice daily, respectively. 6
Additionally, clonidine, an alpha-2 agonist given in doses
of 0.1 to 0.2 mg orally the morning of surgery, has been
shown to be dually benefi cial by decreasing blood pressure
and hence decreasing operative blood loss, and providing
a degree of sedation. 7 Informed consent for the surgical
procedure should be obtained in advance of the surgery,
and many anesthesiologists do not feel that a small dose of
a preoperative anxiolytic will interfere with the patient’s
ability to be adequately consented for an anesthetic.
Ultimately, the perioperative course of a calm, relaxed
patient will more than likely be much smoother than that
of an irritable and anxious patient. 8
TECHNIQUE
Preparation
Upon the patient’s arrival to the surgical suite on the morn-
ing of surgery, both the anesthesiologist and plastic surgeon
should confi rm that no interval changes have occurred
in the patient’s medical condition. If a signifi cant change in
the patient’s health status occurs immediately prior to the
operation, the entire procedure may need to be delayed.
Ostensibly, the paramount concern is patient safety.
After assuring that all the required paperwork and con-
sent forms are in order, the patient may be brought into
the operating room. Prior to the induction of anesthesia, an
intravenous line is inserted for administration of medica-
tions. Intraoperative monitoring is mandated by ASA and
includes continuous EKG monitoring, noninvasive blood
pressure measurements at least every 5 minutes, a pulse
oximeter for measuring oxygen saturation, an end tidal car-
bon dioxide monitor, and the availability of a temperature
probe. Compression boots should be placed on the calves
prior to the induction of general anesthesia as it has been
shown to prevent the incidence of deep vein thrombosis
in patients. 9 A bladder catheter is generally advisable for
cases longer than 4 hours to safely manage fl uid resuscita-
tion, or to keep the bladder decompressed for abdominal
procedures. For procedures that go beyond the expected
time, a catheter can be placed temporarily in the operating
room or postoperative care unit.
Positioning the patient on the operating room table should
take into consideration the risk of permanent nerve injury
from continuous pressure. The patient’s position must allow
the anesthesiologist to have adequate access to the airway
in case there is a problem with ventilation. If the patient’s
face is in the operative fi eld and a problem arises, the airway
should be addressed expeditiously at the temporary expense
of sterility before continuing with the procedure. Finally, the
length and placement of all cords of both electrical devices
as well as patient monitoring systems must be taken into
account. They should be arranged in a fashion that is safe
and do not cause distractions during the surgery.
It is important to note that the temperature of the oper-
ating room is a vital consideration when planning a surgical
procedure. Due to the vasodilatory nature and the direct
inhibition of the hypothalamus caused by many anesthetic
agents, all patients are susceptible to hypothermia or loss
of body heat during surgery. This may result in platelet
dysfunction and bleeding, enzymatic inactivity, cardiac dys-
function, or postoperative shivering. 10 Hence, the ambient
temperature of the operating room should be kept at a
temperature that minimizes body heat loss and a warming
blanket be used for longer procedures as well as warming of
all intravenous fl uids. While hypothermia is probably not a
likely occurrence in short cases, a warming blanket is rela-
tively inexpensive compared with other adjunctive devices.
Both patients and surgeons are interested to know what
role music has in the operating room. In fact, much has
been documented about the use of music before, during,
and after surgical procedures. A recent study found that
patients undergoing a regional anesthetic who listened to
music preoperatively and intraoperatively were calmer
and less preoccupied with their surgical procedure than
were their counterparts. 11 Furthermore, a similar study
reported a measurable difference in heart and respiratory
rates, as well as blood pressures between patients undergo-
ing ambulatory surgery who listened to music compared
with those who did not. 12 Additional studies sought to
determine the effect of music not just on patients, but
on the entire operating room, including the staff and the

ANESTHESIA FOR PLASTIC SURGERY • 63
surgeons. Not surprisingly, the studies showed that listen-
ing to music allayed preoperative anxiety in patients and
neither improved nor hindered the concentration of the
surgeons performing the procedures. 13 Thus, while helping
patients moderate their anxiety, the use of music in the
operating suite seems to be simply a matter of personal
preference and precedent.
Local Anesthesia
Most patients associate surgery with general anesthesia but
other forms of anesthesia exist along the spectrum of choices
for intraoperative sedation/analgesia and can be effectively
used for such procedures. The choice of anesthetic tech-
nique for plastic surgery varies based on the discretion of
the anesthesiologist, the surgeon, and the procedure. Local
anesthesia is useful when the procedure is relatively short
and is addressing a small, localized area of the body.
Local anesthetics are typically injected with a small-bore
needle (23–25 gauge), in the skin and subcutaneous tissues
in the area of the planned procedure. The two classes of
local anesthetics that are commonly used, amino-esters
(procaine, benzocaine) and amino-amides (lidocaine,
bupivicaine), are weak bases that share a similar mecha-
nism of action. Both types provide regional anesthesia by
inhibiting nerve conduction via prevention of the depolar-
izing sodium infl ux into surrounding sensory nerves with
varying duration of action, depending on the chosen anes-
thetic. Potency of local anesthetics is directly correlated to
the lipid solubility of the medication.
Local anesthetics are often combined with epinephrine,
which provides several benefi ts related to regional vaso-
constriction, including improved hemostasis in the area of
infi ltration, and increased duration of action of the anes-
thetic medication. The vasoconstriction effects of epineph-
rine are apparent several minutes after injection. 14
Selection of a local anesthetic is based on the pharma-
cokinetics and pharmacodynamics of each drug as well
as the surgical needs. A combination of local anesthetics
is usually chosen to ensure optimal anesthetic timing for
the procedure. Also, by combining local anesthetics, one
can use less of each drug and limit the possibility of toxic-
ity. Use of a fast-acting anesthetic with a short duration of
action, such as lidocaine (onset 1–2 min, duration 1–4 h),
with a slower-acting agent with an extended duration, such
as bupivicaine (onset 5 min, duration 2–8 h), is a common
practice. 12 Additionally, sodium bicarbonate may be added
to the solution to both hasten the onset of action of the
local anesthetic and decrease the pain associated with the
infi ltration of the medication into the tissues. 15
Local anesthetics are not without risk and should be
dosed appropriately according to the weight of the patient.
The maximum dose of lidocaine is 5 mg/kg patient weight,
and 7 mg/kg patient weight when combined with epineph-
rine. Allergy to local anesthetics is rare, and is more com-
mon with the ester-type anesthetics. Practitioners should be
aware of the systemic toxicities associated with local anes-
thetics and how to treat them, should these complications
arise. A common cause of local anesthetic toxicity is inad-
vertent intravascular injection of the medication. Signs of
toxicity may be limited to relatively harmless symptoms,
including circumoral numbness, restlessness, and tinnitus,
but may progress to more serious conditions, including sei-
zures, hypotension, myotonia, respiratory failure, cardiac
arrhythmias, myocardial depression, and coma. Treatment
of these symptoms includes benzodiazepines for control
of seizures, endotracheal intubation for respiratory failure,
epinephrine with calcium channel blocking agents for car-
diac arrhythmias, or in cases involving bupivicaine, a 20%
Intralipid infusion for cardiovascular collapse. 13 Further up
to date information and directions for the use of Intralipid
can always be found on the website
squarespace.com. 14
Local anesthetics are useful for providing regional anes-
thesia, and may prove to be especially helpful in the setting
of a small offi ce-based procedure. Eliminating the need for
sedation or general anesthesia has both safety and economic
benefi ts. This technique puts the patient at less risk from
sedation, reduces the cost of the procedure, and reduces
the time required to complete the surgery. However, all
practitioners should be cautious when using these medi-
cations and bear in mind the potentially dangerous side
effects that can occur with both inadvertent intravascular
injections or exceeding the therapeutic dosages.
Monitored Anesthetic Care
The technique of monitored anesthesia care (MAC) uses a
combination of local anesthesia, intravenous analgesia, and
sedative medications. Although MAC does not correlate
with any specifi c depth of anesthesia (rather it refers to
sedation administered by a professional anesthesia practi-
tioner), it usually refers to a depth of sedation with a “min-
imally depressed level of consciousness that retains the
patient’s ability to maintain an airway independently and
continuously and to respond to physical stimuli and verbal
commands.” 16,17 This level of sedation will provide for a
patient that is sedated and will not have any keen sense of
environmental awareness. However, unlike in general anes-
thesia where unconsciousness is induced and spontaneous
respiration is depressed, patients will continue to breathe
on their own.
Monitored anesthetic care has been shown to be effec-
tive and safe in large study populations. 18-20 Typically,
a combination of two or more medication types is used
to achieve the desired level of sedation and analgesia.
Commonly used agents include rapid acting drugs such as
fentanyl, midazolam, and propofol. 21,22
As previously mentioned, anesthetic depth is a contin-
uum and thus the administration of high dosages of seda-
tive medications will cause the patient to ultimately lose
protective airways refl exes and move into a state of general
anesthesia. In some instances, this will require securing the
airway, and in others it may require assistance in maintain-
ing a patent airway while decreasing the dose of the anes-
thetic agents to allow the patient to regain spontaneous

64 • CHAPTER 6
respiration. For this reason, monitored anesthesia care
has all of the same perioperative requirements as general
anesthesia. Patients should be screened preoperatively, vig-
ilantly monitored intraoperatively according to ASA stan-
dards, and meet the same discharge criteria. Emergence
from monitored anesthesia care will be discussed below.
General Anesthesia
“General anesthesia is defi ned as a controlled state of
unconsciousness accompanied by a loss of protective air-
way refl exes [in addition to] the inability to maintain a
patent airway the patient will be unresponsive to verbal
commands.” 23 With this type of anesthesia, the patient may
require respiratory or cardiovascular support. The inser-
tion of an endotracheal tube after induction will allow
control of ventilation. Throughout the surgical procedure,
the patient is closely monitored to note any changes in
physiologic status (eg, oxygen saturation, blood pressure,
heart rate and rhythm, breathing rate and rhythm, and
temperature). General anesthesia can be divided into three
phases: induction (when the patient loses consciousness),
maintenance (when unconsciousness is maintained during
the procedure), and emergence (when the patient regains
consciousness).
Induction
Understandably, a smooth induction with minimal hyper-
tension and tachycardia is desirable for cosmetic anesthe-
sia. Prior to induction, the anesthesiologist should consider
a number of premedications. Midazolam, a short-acting
benzodiazepine, can produce sedative-hypnotic effects or
can even induce anesthesia at very high doses. It is also
characterized by its ability to cause amnesia, hypnosis, and
the relaxation of muscles with relative celerity. In fact, the
onset of sedation following intravenous administration of
midazolam is usually within 1 to 3 minutes, though there
is some degree of patient variability. Intravenous mida-
zolam will depress the ventilatory response to carbon
dioxide stimulation, which may already be impaired in
patients with chronic obstructive pulmonary disease. In
young, healthy patients, intravenous sedation with mida-
zolam alone in small doses does not appear to adversely
affect respiration. As far as cardiac sensitivity is concerned,
the use of midazolam is associated with decreases in mean
arterial pressure, cardiac output, stroke volume, and sys-
temic vascular resistance. Consequently, midazolam is
relatively contraindicated in patients with acute pulmonary
insuffi ciency or severe chronic obstructive pulmonary disease .
Nevertheless, studies have reported that the administra-
tion of certain barbiturate and benzodiazepine drugs by
an anesthesiologist preoperatively may “reduce the overall
anesthetic requirements [of the procedure itself], thereby
improving recovery time [later].” 24
Postoperative nausea and vomiting (PONV) is a major
concern with any anesthetic procedure. Preoperative anti-
emetics should be used to prevent PONV following the
use of numerous anesthetic agents, including narcotics and
nitrous oxide. Many anesthesiologist avoid narcotics alto-
gether to minimize the incidence of PONV. Alternative
analgesics include local anesthetics, ketamine, and ketoro-
lac. Others still advocate the use of narcotics for painful
procedures and utilize a variety of available antiemetics to
minimize PONV. Granisetron (0.2–1 mg IV) and ondanse-
tron (1–4 mg IV) are serotonin antagonists that reduce the
autonomic neuro-activity in the vomiting center of the
brain. Dexamethasone (4–10 mg IV), a steroid, and sco-
polamine, a tropane alkaloid, both may be used to resolve
dizziness and nausea. Fosaprepitant dimeglumine, a newer
antiemetic, is increasingly being used. 25,26 Multimodal ther-
apy using several antiemetics is advisable for patients with
a high risk for PONV. These patients would include young
women, nonsmokers, those with a history of PONV or car
sickness, and patients undergoing breast, gynecologic, or
laparoscopic surgery. 27
Various drugs can be used to induce general anesthesia.
One commonly used induction agent is propofol, a short-
acting intravenous drug used in adult and pediatric patients.
It may also be used during the procedure for the mainte-
nance of anesthesia. Side effects include hypotension and
apnea following induction, as well as pain on injection,
which can be ameliorated by pretreatment with intrave-
nous lidocaine. 28 Propofol is often used for cosmetic pro-
cedures because it is associated with reduced PONV and
can even be used as an antiemetic. Thiopental is another
induction agent. Thiopental is a barbiturate that affects
fi ne motor skills and is notorious for producing a heavy
“hangover” effect and signifi cant PONV. 29 Midazolam and
ketamine can also be used for induction, although they
are associated with a longer recovery time postoperatively.
Ketamine, a phencyclidine derivative, is an anesthetic agent
approved for human and veterinary use, whose popularity
in the outpatient arena has increased over the past several
years. 30 Its effects include analgesia and sedation with min-
imal to no respiratory depression. However, hallucinations,
hypertension, increased intracranial pressure and salivation
have limited its appeal. It has been used successfully with
propofol and midazolam for cosmetic procedures since it
may be used without the need for endotracheal intubation,
supplemental oxygen, or narcotics. 31
Airway Protection
General anesthesia requires control of the patient’s airway.
The drugs used to induce unconsciousness are often associ-
ated with muscle weakness, and the loss of many autonomic
refl exes, including the ventilatory response to carbon diox-
ide and hypoxia. 32 Thus, patients under general anesthe-
sia often require mechanical ventilation. Adequate airway
control may be achieved either with a traditional endo-
tracheal tube (ETT) that passes beyond the vocal cords
or with a laryngeal mask airway (LMA) that is infl ated
above the vocal cords at the laryngeal aperture. As with
all considerations in cosmetic surgery, the means of secur-
ing the airway depends on the procedure being performed.

ANESTHESIA FOR PLASTIC SURGERY • 65
For procedures that do not involve frequent head turning,
the LMA provides a safe alternative to the ETT since it
does not risk vocal cord injury and has less of an incidence
of postoperative laryngeal irritation and “bucking on the
tube.” 33 However, since the LMA does not occlude the tra-
chea, patients at high risk for aspiration should still use a
traditional ETT.
The device itself may be secured to the face in various
ways. For procedures not involving the face, adhesive tape
is most often used to secure the tube to the maxilla. For
facial procedures, the tube may be prepped into the fi eld
or covered with sterile plastic or stockinet to maintain ste-
rility. Of paramount importance is that the surgeon and
anesthesiologist weigh surgical exposure versus sterility
and always respect the need for emergent visualization of
the numerous connections within the patient’s anesthetic
breathing circuit should problems with ventilation arise.
Because surgical preparation of the face often dislodges
the tape holding the tube, it may be advisable to place a
suture around the tube and then around the teeth in the
midline. Of course, this is impractical in patients with den-
tal restoration, such as a bridge or an implant.
Following the induction of general anesthesia, the anes-
thesiologist must vigilantly monitor changes in the patient’s
cardiovascular status, including alterations in oxygen satu-
ration, blood pressure, heart rate and rhythm, respiratory
rate, and temperature, while continuously administrating
anesthetics for the duration of the operation. To accom-
plish this, the anesthesiologist carefully administers a com-
bination of drugs while closely assuring that the patient’s
heart rate and blood pressure are well controlled.
A constant stable blood pressure in the low-normal
range for the duration of the cosmetic procedure is desir-
able to minimize blood loss and bleeding into the tissues
that contributes to prolonged postoperative ecchymo-
sis and edema. More severe consequences of prolonged
hypertension include cardio-pulmonary-hepatic conges-
tion or anasarca, and possibly even heart or renal failure.
If the blood pressure drops too low, the patient will not
adequately perfuse vital organs and can develop circula-
tory collapse.
The choice of drugs used to maintain anesthesia is also
important to minimize PONV and allow for a rapid recov-
ery process. Nitrous oxide has been historically used as an
inhalational agent, in conjunction with other volatile or
intravenous anesthetics, to maintain anesthesia. Nitrous
oxide reduces the need for higher concentrations of these
other volatile inhalational agents. It is, however, associ-
ated with PONV and should be limited to concentrations
under 50%. 34
Isofl urane is one of a number of volatile inhalation
agents commonly used for maintenance of anesthesia.
Desfl urane is shorter-acting member of this class of drugs
and may be more suitable for plastic and ambulatory sur-
gery. Its quick recovery time results from a higher vapor
pressure. However, desfl urane often causes postoperative
respiratory irritation and coughing largely due to its pun-
gent smell. Sevofl urane is better tolerated than desfl urane
since it lacks a characteristic odor. As a result of the lower
solubility of these newer volatile agents, cognitive func-
tions return to baseline more rapidly when compared with
inhaled isofl urane.
Continuous intravenous anesthetics are commonly
employed in cosmetic surgery. Propofol, remifentanil, dex-
medetomidine, and ketamine are among the most com-
monly used. Propofol was discussed earlier as a drug of
choice for induction, but can also be used as a continu-
ous infusion (75–150 mg/kg/min) to maintain anesthesia.
Remifentanil may be used just prior to induction to sup-
press the autonomic responses to intubation and during
maintenance to suppress other autonomic responses to
surgical stimuli. Because it is also an ultra short-acting nar-
cotic, it is ideal for the end of the procedure since it is
a potent cough suppressant. However, as with all narcot-
ics, it can cause PONV. 35 It must also be appreciated that
since remifentanil is so short acting, it will not produce
any signifi cant postoperative analgesia. Last, ketamine, like
propofol, can be used for both induction and maintenance,
though it is often associated with an increase in blood
pressure and salivation, as well as bad hallucinations. The
dysphoria associated with ketamine can be ameliorated
with the concomitant use of midazolam and propofol.
Fortunately, ketamine is not associated with PONV.
Emergence
Emergence should be a well-planned event. The ideal emer-
gence from anesthesia following cosmetic surgery would
not be associated with an increase in blood pressure or
heart rate, there would be no “bucking on the tube” from
irritation of the trachea by the endotracheal tube, and no
respiratory complications. 36 While the concentration of
inhalational and intravenous anesthetics are lowered to
allow the patient to regain consciousness, additional medi-
cations are administered to restore muscle strength to allow
the patient to breathe spontaneously and to permit extuba-
tion. Maneuvers that are particularly stimulating, such as
nasogastric decompression or suctioning, are done while
the patient is still deeply sedated to prevent hypertension.
Gagging at the conclusion of any procedure is undesirable
because it raises blood pressure and may trigger subcuta-
neous bleeding. The prevention of nausea and vomiting
is important to minimize fl uctuations in blood pressure.
Patients should be reminded as they emerge from anesthesia
that they may have blurred vision due to the ointment and
should be prevented from attempting to rub their eyes.
General Anesthesia Compared
with Monitored Anesthesia Care
Each of the aforementioned anesthetic techniques has
both advantages and disadvantages, thus the selection of
one method over the other truly depends on the nature
of the surgical procedure and the comfort level of the
anesthesiologist and surgeon alike.
For shorter, less complicated procedures, either method
of general or monitored care may be used. For diffi cult and

66 • CHAPTER 6
time-consuming procedures, general anesthesia is often
more appropriate. In the monitored anesthesia care model,
the patient drifts in and out of consciousness during the
procedure and may become more anxious, irritable, and
emotional than patients undergoing general anesthesia. 37
PONV, however, may be reduced.
It should be noted that the administration of both types
of anesthesia in an ambulatory setting are safe. Largely due
to the meticulous preoperative screening and technologi-
cal advancements in anesthesia, morbidity and mortality
resulting from outpatient anesthesia are rare. 38 A recent
study reported no signifi cant differences between either
form of anesthetic technique employed as it relates to
patient recovery time, sensitivity to pain, and safety. 39 A
joint study conducted by Yale University and the State
University of New York at Stony Brook evaluated the safety
of outpatient anesthesia for plastic surgery procedures on
the face. The study reported no deaths or severe complica-
tions among the 1200 cases retrospectively reviewed. 40
Patients undergoing cosmetic surgery are generally well
informed regarding the nature of the procedure and the
reputation of their surgeon, but overlook the importance
of the anesthetic technique needed to effectively perform
the procedure. A successful cosmetic procedure involves
both a skilled plastic surgeon and a knowledgeable anes-
thesiologist. Cosmetic surgeons realize the importance
of this and often choose to work with one or more select
anesthesiologists with whom they have developed a rap-
port and a tacit understanding of what is needed before,
during, and after surgery.
COMPLICATIONS
After the induction of general anesthesia, every effort
should be made to protect the patient’s eyes and cornea
specifi cally from inadvertent injury. Closed eyes must
always remain closed during surgery, especially procedures
on the face. With the various surgical instruments being
passed between the nurse and surgeon, accidents may
occur. To minimize the risk of corneal abrasion, a gentle
ophthalmologic lubricant, with or without antibiotic
placed in the lower fornix of each eye at the start of the
procedure, may be helpful. Sterile tapes are also recom-
mended to keep the eyelids closed if possible. 41 Ointment
is not easily washed from the eye, so that unlike tape that
may come loose during the procedure, ointment tends to
remain for the duration.
Episodes of prolonged, excessive hypertension under
anesthesia can cause congestion in the heart, lungs, and liver,
leading to anasarca and possibly organ failure. Conversely,
if the blood pressure drops too low, the patient will not
adequately perfuse vital organs and can develop circula-
tory collapse. Keeping the blood pressure constant at a
level that ensures adequate perfusion without the afore-
mentioned complications cannot be overemphasized.
As noted, PONV is a major concern with any anes-
thetic procedure. Strategies to prevent or minimize PONV
include the use of preoperative antiemetics and the avoid-
ance of narcotics in lieu of alternative analgesics such as
local anesthetics and ketorolac. Available antiemetics
include the serotonin antagonists granisetron and ondanse-
tron, the steroid dexamethasone (4–10 mg IV), the alka-
loid scopolamine, and fosaprepitant, as well as combination
therapy.
OUTCOMES
Anesthetic care does not end once the endotracheal tube
has been removed and the patient is restored to conscious-
ness. Patients must be closely monitored postoperatively
for signs and symptoms of hypoxia, hypertension, pain,
PONV, and even unconsciousness. This is an important part
of the continuum of anesthesia care. A patient may be dis-
charged once an assessment of home readiness test is con-
ducted. 38 In this evaluation, patients are closely observed
to ensure that their vital signs are stable, to make sure they
are environmentally aware, and to make sure they can walk
without falling or becoming excessively dizzy. Patients are
also evaluated for pain, PONV, and bleeding at the surgi-
cal site. Most delays in discharge are due to pain, PONV,
hypotension, and dizziness upon ambulating. 38 All patients
require analgesia postoperatively, and some may require
stronger medications than acetaminophen or NSAID-type
drugs as part of their postoperative regimen.
1. 2000/2005/2006 National Plastic Surgery Statistics. American
Society of Plastic Surgeons.
2. Zukowski ML, Ash K, Klink B, et al. Breast Reduction under
intravenous sedation: A review of 50 cases. Plast Reconstr
Surg . 1997;99(1):256.
3. American Society of Anesthesiologists. Continuum of Depth
of Sedation: Defi nition of General Anesthesia and Levels of
Sedation/Analgesia. 21 Oct. 2009.
For-Members/Standards-Guidelines-and-Statements.aspx;
2009.
4. ASA Physical Status Classifi cation System. American Soci-
ety of Anesthesiologists.
physicalstatus.htm.
5. Practice guidelines for preoperative fasting and the use of
pharmacologic agents to reduce the risk of pulmonary aspi-
ration: application to healthy patients undergoing elective
procedures: a report by the American Society of Anesthe-
siologist Task Force on Preoperative Fasting. Anesthesiology .
1999;90(3):896.
6. Rankin MK, Borah G. Anxiety disorders in plastic surgery.
Plast Reconstr Surg . 2004;113(7):2199.
7. Taittonen M, Kirvelä O, Aantaa R, Kanto J. Cardiovascular and
metabolic responses to clonidine and midazolam premedi-
cation.

9088819. Eur J Anaesthesiol. 1997;14(2):190–196.
REFERENCES

ANESTHESIA FOR PLASTIC SURGERY • 67
8. Pearson S, Maddern GJ, Fitridge R. The role of pre- operative
state-anxiety in the determination of intra-operative neu-
roendocrine responses and recovery.
library.mssm.edu:2060/pubmed/15969856. Br J Health
Psychol. 2005;10(Pt 2):299–310.
9. Okuda Y, Kitajima T, Egawa H, et al. A combination of
heparin and an intermittent pneumatic compression device
may be more effective to prevent deep-vein thrombosis in
the lower extremities after laparoscopic cholecystectomy.
Surg Endosc . 2002;5:781.
10. Rundgren M, Engström M. A thromboelastometric evalua-
tion of the effects of hypothermia on the coagulation system.
Anesth Analg . 2008;107(5):1465.
11. Eisenman A, Cohen B. Music therapy for patients undergo-
ing regional anesthesia. AORN J . 1995;62(6):947.
12. Augustin P, Hains AA. Effect of music on ambulatory sur-
gery patients’ preoperative anxiety. AORN J . 1996;63(4):
750,753–758.
13. Sármány J, Kálmán R, Staud D, Salacz G. Role of the music
in the operating theatre.” Orv Hetil . 2006;147(20):931.
14. Liu SS, Lin Y. Local anesthetics. In: Barash PG, Cullen BF,
Stoelting RK, et al., eds. Clinical Anesthesia. Philadelphia,
PA: Lippincott Williams & Wilkins; 2009:541.
15. Palmon SC, Lloyd AT, Kirsch JR. The effect of needle gauge
and lidocaine pH on pain during intradermal injection.
Anesth Analg . 1998;86(2):379.
16. Stevens MH, White PF. Monitored anesthesia care. In:
Miller RD, ed. Miller’s Anesthesia. 4th ed. Philadelphia, PA:
Churchill Livingstone; 1994:1465–1480 [Chapter 44].
17. Task
Force
on
Sedation
and Analgesia
by
Non-
Anesthesiologists. Practice guidelines for sedation and
analgesia by non-anesthesiologists: An updated report by
the American Society of Anesthesiologists Task Force of
Sedation and Analgesia by Non-Anesthesiologists. Anesthe-
siology . 2002;4:1004.
18. Bitar G, Mullis W, Jacobs W, et al. Safety and effi cacy of
offi ce based surgery with monitored anesthesia care/seda-
tion in 4778 consecutive plastic surgery procedures. Plast
Reconstr Surg . 2003;111:150.
19. Kryger ZB, Fine NA, Mustoe TA, et al. The outcome of
abdominoplasty performed under conscious sedation: six-
year experience in 153 consecutive cases. Plast Reconstr Surg .
2004;113:1807.
20. Marcus JR, Tyrone JW, Few JW, et al. Optimization of
conscious sedation in plastic surgery. Plast Reconstr Surg .
1999;104(5):1338.
21. Cinella G, Meola S, Portincasa A, et al. Sedation analge-
sia during offi ce-based plastic surgery procedures: com-
parison of two opioid regimens. Plast Reconstr Surg . 2007;
119(7):2263.
22. Yoon HD, Yoon ES, Dhang ES, et al. Low-dose propofol
infusion for sedation during local anesthesia. Plast Reconstr
Surg . 2002;109:956.
23. Nique TA. Ambulatory offi ce general anesthesia. In: Nique
TA, Tu HK, eds. Anesthesia for Facial Plastic Surgery . New
York: Thieme Medical Publishers; 1993.
24. Reves JG, Glass PSA, Lubarsky DA. Nonbarbiturate intra-
venous anesthetics. In: Miller RD, ed. Miller’s Anesthesia.
4th ed. Philadelphia, PA: Churchill Livingstone; 1994:
247–290 [Chapter 11].
25. Kolodzie K, Apfel CC. Nausea and vomiting after offi ce-
based anesthesia. Curr Opin Anaesthesiol . 2009;22(4):
532.
26. Gray H. Aprepitant for postoperative nausea and vomiting.
Anaesth Intensive Care . 2009;37(1):135.
27. Gan, TJ Meyer TA, Apfel CC, et al. Society for Ambulatory
Anesthesia guidelines for the management of postoperative
nausea and vomiting. Anesth Analg . 2007;105(6):1615.
28. Piper SN, Röhm KD, Papsdorf M, et al. Dolasetron reduces
pain on injection of propofol [German]. Anasthesiol Inten-
sivmed Notfallmed Schmerzther . 2002;37(9):528.
29. Fragen RJ, Avram MJ. Barbiturates. In: Miller RD, ed. Miller’s
Anesthesia. 4th ed. Philadelphia, PA: Churchill Livingstone;
1994:229–246 [Chapter 10].
30. Friedberg BL. Facial laser resurfacing with the propofol-
ketamine technique: room air, spontaneous ventilation
(RASV) anesthesia. Dermatol Surg . 1999;25(7):569.
31. Friedberg BK. Propofol-ketamine technique: dissociative
anesthesia for offi ce surgery (a fi ve year review of 1,264
cases). Aesthetic Plast Surg . 1999;23:70.
32. Knill RL, Clement JL. Variable effects of anesthetics on the
ventilatory response to hypoxia in man. Can Anaesth Soc J .
1982;29:93.
33. Cork, RC, Depa MC, Standen JR. Prospective comparison of
use of the laryngeal mask airway an endotracheal tube dur-
ing ambulatory anesthesia. Anesth Analg . 1994;79:719.
34. Moffi tt EA, Sethna DH, Gary RJ, et al. Nitrous oxide added
to halothane reduces coronary fl ow and myocardial oxygen
consumption in patients with coronary disease. Can Anaesth
Soc J . 1983;30:5.
35. Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinet-
ics of the new short-acting opiod remifentanil (G197084B)
in healthy adult male volunteers. Anesthesiology . 1993;
79(5):881.
36. Koga K, Asai T, Vaughan RS, Latto IP. Respiratory com-
plications associated with tracheal extubation. Timing of
tracheal extubation and use of the laryngeal mask airway
during emergence from anesthesia. Anaesthesia . 1998;
53(6):540.
37. Boskovski, N. Regional anesthesia. In: Nique TA, Tu HK,
eds. Anesthesia for Facial Plastic Surgery . New York: Thieme
Medical Publishers; 1993.
38. Ostman PL, White PF. Outpatient anesthesia. In: Miller RD,
ed. Miller’s Anesthesia. 4th ed. Philadelphia, PA: Churchill
Livingstone; 1994:2213–2246 [Chapter 69].
39. Hasen KV, Samartzis D, Casas LA, Mustoe TA. An outcome
study comparing intravenous sedation with midazolam/
fentanyl (conscious sedation) versus propofol infusion
(deep sedation) for aesthetic surgery. Plast Reconstr Surg .
2003;112(6):1683.
40. Gordon NA, Koch ME. Duration of anesthesia as an indica-
tor of morbidity and mortality in offi ce-based facial plastic
surgery. Arch Facial Plast Surg . 2006;8:47
41. Orlin SE, Kurata FK, Krupin T, et al. Ocular lubricants
and corneal injury during anesthesia. Anesth Analg . 1989;
3:384.

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7
Malignant Skin Lesions
Wesley N. Sivak, MD, PhD / Roee E. Rubinstein, MD / Howard D. Edington, MD, MBA
c h a p t e r
PATIENT EVALUATION AND SELECTION
The initial evaluation of any cutaneous lesion must include
an assessment of a patient’s risk factors for malignancy.
Lifetime sun exposure should be estimated through a
detailed patient history. Determination of a patient’s
Fitzpatrick skin type ( Table 7-1 ) is a useful method of
stratifying patients based on their sunburn and tanning
history, and patients with type I and II skin are at signifi -
cantly higher risk of developing cutaneous malignancies. 1
Likewise, a personal or family history of skin cancer dra-
matically increases an individual’s risk, and should be con-
sidered and documented. 2
Once an individual’s personal and family histories have
been considered, the natural history of any lesion in ques-
tion should be explored in further detail. The American
Cancer Society’s “ABCD” criteria are useful for assessing
potential malignancies ( a symetry, b order irregularity, c olor
variegation, d iameter .6 mm). Any change in size, shape,
or color of a previously stable pigmented lesion warrants
close observation or preferably biopsy. New pigmented
lesions appearing in older patients are highly suspicious,
as most benign acquired nevi have developed by age
40 years. Bleeding, scaling, and ulceration are concerning
signs often associated with invasion. The clinical diagnosis
is confi rmed with appropriate biopsy. If the diagnosis of
melanoma is entertained, the biopsy must be full thickness
to allow accurate measurement of the thickness of the pri-
mary (Breslow depth in mm) which has prognostic impor-
tance and directs appropriate treatment. An incisional or
excisional biopsy is appropriate, whereas a shave biopsy is
to be avoided.
Melanoma
Melanoma is currently the sixth most frequently diagnosed
cancer in the United States. Although the National Cancer
Institute recognizes nonmelanoma skin cancer as the most
common cancer in the United States the overall mortality
from melanoma is three times higher than from all other
cutaneous malignancies combined. 3 Melanoma tends to
occur on body surfaces that receive at least occasional sun
exposure. Exposures and behaviors in childhood and early
adulthood are particularly critical in determining lifelong
risk of melanoma. The disease mostly affects Caucasians,
with rates substantially lower in Asian and Hispanic popu-
lations; melanoma is rare among black persons.
There is strong evidence for the importance of intense,
intermittent sun exposure vs cumulative exposure in the
etiology of melanoma. 4 The size, type, and number of
nevomelanocytic nevi on the skin have been consistently
associated with melanoma risk to a greater degree than any
direct measure of sun exposure. 5 Atypical nevi are thought
to be both markers of elevated risk and melanoma precur-
sors; however, as many as half of all melanomas arise in
individuals who are unaffected by these lesions. A small
percentage (3%–5%) of lesions appear to occur in individ-
uals with inherited risk. 6 Primary cutaneous melanomas
have been classifi ed into four subtypes based on growth
pattern with each having distinct phenotypic and histo-
logical features. While these features defi ne and distinguish
the melanoma subtypes, the key unifying element is that
tumor thickness is an important prognostic factor for all
melanomas. This again underscores the importance of an
early diagnosis
Superfi cial Spreading Melanoma (SSM). The most
common type of cutaneous melanoma, accounting for
70% of all cases diagnosed, most commonly occurs on the
legs and back in women, and on the upper back in men
(though it can occur in any location) . The peak incidence
of SSM is in the fourth and fi fth decades, earlier than other
melanoma subtypes. SSM may initially present as a deeply
pigmented asymmetric macule or slightly raised plaque,
and may appear as a new lesion or as a focal darkening

70 • CHAPTER 7
within an existing nevus ( Figure 7-1 ). SSM is the variant
of melanoma most likely to arise within or in continuity
with a preexisting melanocytic nevus. During the radial
growth phase, which may last months to years, it usually
develops asymmetry and border irregularities that may
raise suspicion in the patient or physician. Color variega-
tion is characteristic of SSM, and hypopigmented areas of
regression may be evident. If left undetected or untreated,
the lesion transitions into a vertical growth phase, heralded
by papular or nodular changes within the lesion, and the
melanoma can become deeply invasive. It is often at this
stage that the patient may bring the lesion to the attention
of the physician. Biopsy is imperative.
Nodular Melanoma (NM). The second most common
form of melanoma, with a frequency of 15% to 30% of all
TABLE 7-1. Fitzpatrick’s Classifi cation of
Sun-reactive Skin Types
Skin Type
Skin Color
Characteristics
I
White; very fair; red or
blond hair; blue eyes;
freckles
Always burns,
never tans
II
White; fair; red or blond
hair; blue, hazel, or
green eyes
Usually burns,
tans with
diffi culty
III
Cream white; fair with
any eye or hair color;
very common
Sometimes burns,
gradually tans
IV
Brown; typical
Mediterranean
Caucasian skin
Rarely burns,
tans with ease
V
Dark brown; Middle
Eastern skin types
Rarely burns, tans
easily
VI
Black
Never burns, tans
easily
FIGURE 7-1. Superfi cial spreading melanoma: Elements
of the ABCD criteria are evident. Initial management requires
excisional or incisional biopsy.
FIGURE 7-2. Nodular melanoma: Homogenous
pigmentation and nodular appearance.
cases diagnosed, favors individuals in their fi fth and sixth
decades, and may arise within existing nevi or de novo. NM
exhibits rapid expansion and progression without an iden-
tifi able radial growth phase, and may be deeply invasive
at the time of initial diagnosis. Clinically, NM presents as
an enlarging papule, nodule, or pedunculated lesion, often
with a history of bleeding, and may measure 1 to 2 cm
in diameter. Distinct from other types of melanoma, NM
often lacks color variegation, appearing typically as a uni-
form dark blue-black, steel gray, blue-red, or amelanotic
nodule, with or without superfi cial ulceration ( Figure 7-2 ).
The amelanotic melanoma may appear clinically innocuous
and is readily misdiagnosed or overlooked. The differential
diagnosis includes hemangioma, pyogenic granuloma, blue
nevus, and pigmented basal cell carcinoma. Nodular mela-
nomas are highly aggressive and the diagnosis must be con-
sidered in any rapidly growing cutaneous nodule.
Lentigo Maligna Melanoma (LMM). Lentigo maligna
melanoma rises from an in situ (intraepidermal) precursor
( Figure 7-3A,B ). In situ melanomas have not yet invaded
the basement membrane ( Figure 7-3B ); have a very low
metastatic potential; and should be excised with 5 mm
margins. Lentigo maligna (LM) comprises 4% to 10% of
all melanomas. LM presents as a macule or patch with
variegated brown-black pigmentation in a sun-exposed
area ( Figure 7-4 ) The differential diagnosis includes solar
lentigo and seborrheic keratosis, as well as pigmented
actinic keratosis. LM lesions undergo a slow, progressive

MALIGNANT SKIN LESIONS • 71
enlargement during a prolonged radial growth phase, often
over many years, but can progress rapidly once the verti-
cal growth phase is initiated. Vertical growth into the der-
mis and development of invasive LMM are often heralded
by intralesional dark papules and/or indurated nodules
( Figure 7-4 ). The margins of LM and LMM often extend
well beyond the clinical area of pigmentation, and sur-
rounding skin is often actinically damaged, making histo-
logic evaluation diffi cult. LMM, when compared to other
melanoma types, has the lowest propensity for metastasis
and the best prognosis. Despite this, the lifetime risk of
invasive melanomatous change is estimated at 30% to 50%
and surgical excision of LM is recommended. 7
Acral Lentiginous Melanoma (ALM). Acral lentigi-
nous melanoma is relatively rare, accounting for 2% to
8% of melanomas diagnosed. ALM is the most common
form of melanoma in dark-skinned individuals, represent-
ing 70% of melanomas in blacks and up to 46% in Asians.
B
A
FIGURE 7-3. (A) In situ melanoma: Clinical appearance. (B) In situ melanoma:
Pathology confi rms intraepithelial location without invasion.
FIGURE 7-4. Lentigo maligna melanoma: This lesion
involves an extremity. The bulk of this lesion is in situ disease.
Note the nodular component representing invasive changes
and note also depigmented areas of regression.
Its incidence peaks in the seventh decade of life, and it is
usually diagnosed late due to delayed presentation. These
lesions involve the plantar or palmar skin and may occur
in the subungual location. They are often misdiagnosed as
fungal infections and biopsy is frequently delayed for up
to a year at which point the disease is often in an advanced
stage with no realistic hope for cure—again, emphasizing
the need for a high index of suspicion and low threshold
for biopsy. Subungual lesions require removal of the nail
for accurate biopsy ( Figure 7-5A,B )
Nonmelanoma Skin Cancer
Nonmelanoma skin cancer (NMSC) is the most commonly
diagnosed malignancy in the United States, accounting
for 33% to 50% of all newly diagnosed cancers each year.
More than 1 million new cases are diagnosed in the United
States and 3 million in the world every year. Basal cell car-
cinoma (BCC) (75%) and squamous cell carcinoma (SCC)
(20%) account for the vast majority of NMSC (.95%).
Because of their slow growth and negligible risk for metas-
tasis, the mortality associated with these cancers is low;
however, they cause considerable functional and cosmetic
deformity.
A number of genetic disorders exist that are charac-
terized by an increased incidence of NMSC. Xeroderma
pigmentosum is a rare autosomal recessive disorder (prev-
alence 1:250,000) characterized by a defect in the normal
detection and repair mechanism of the UV-induced DNA
damage.
Nevoid basal cell syndrome (or Gorlin syndrome) is a
multisystemic disorder characterized by the occurrence of
multiple BCC often in the hundreds, odontogenic cysts of
the jaw, calcifi cation of the falx cerebri, pitting in the palms
and soles, and various skeletal abnormalities (bifi d ribs, bra-
chymetacarpalism, broad nasal root, and overdeveloped
supraorbital rim). BCCs usually develop between the sec-
ond and third decade and distant metastasis is rare. Other
genetic syndromes that predispose to skin carcinoma include

72 • CHAPTER 7
albinism (increased risk of SCC), porokeratosis (13% chance
of SCC formation), and epidermodysplasia verruciformis.
A number of skin lesions are also associated with the
development of NMSC, and understanding the associated
risk of malignant degeneration facilitates management of
the patient. Actinic keratosis is the most common prema-
lignant lesion, as it develops in 16% of North American
Caucasians during their lifetime. The transformation rate
to SCC ranges between 10% and 13%. Nevus sebaceous of
Jadassohn is a well-circumscribed, raised, yellowish plaque
that is present at birth on the scalp and face; degeneration
into BCC is seen in 5% to 10% of cases. The cutaneous
horn is a hard keratotic growth that is taller than its base,
and the incidence of an underlying squamous cell carci-
noma is thought to be about 10%. Specifi c defi ciencies
of cell-mediated immunity are also correlated with the
development of BCC and SCC. Advanced and or extensive
NMSCs are associated with low T cell levels and apparent
tumor anergy. Patients receiving chronic immunosuppres-
sive therapy have a 50% risk of developing SCC within
20 years of transplantation; 30% of such cancers are con-
sidered highly aggressive.
Basal Cell Carcinoma . BCC is the most common malig-
nancy among whites, and its incidence shows clear geo-
graphic variation refl ecting the likelihood of signifi cant
sun exposure. Among Caucasians in North America, the
incidence has increased at more than 10% a year, leading
to a lifetime risk of 30% of developing BCC. Patients with
BCC have an increased risk of developing a second BCC of
the skin (35% at 3 years, 50% at 5 years), which increases
with number of previous skin cancers, solar damage, and
skin sensitivity. Histologic type correlates with malignant
potential and recurrence and suggests wider clinical mar-
gins of resection.
Nodular BCC. The most common BCC subtype (50%–
55%), it presents as a small solitary nodule or papule on the
surface of the skin of the face with a shiny, pearly, trans-
lucent appearance and often small or large telangiectatic
vessels traversing throughout. The nodule is round or oval,
and the depth is usually similar to the width. Over time,
the clinical picture may be dominated by central ulceration
surrounded by a rolled pearly border and bleeding, thus
masking the nodularity (“rodent ulcer”). Although most
are red or fl esh colored, they may show variable amounts
of pigmentation mimicking or even masking underlying
melanoma.
Superfi cial BCC. The second most common BCC type
(10%) presents as an erythematous, fl aking lesion usually
containing superfi cial ulcerations or crusting. The borders
are usually round or oval, although they may be irregu-
lar. The lesions tend to occur mostly in the trunk. They
are indolent and may be confused with a variety of benign
disorders, including psoriasis, eczematous dermatitis, and
Bowen disease (in situ SCC; see below). Excision may be
incomplete because the tumor may extend beyond the
clinical margin or because the margin may be obscured
by erythema from associated infl ammation. Typically, the
tumor is confi ned to the epidermis, and growth is more
radial than vertical.
A
B
FIGURE 7-5. (A) Subungual melanoma: Note pigmentation of the nail which is
consistent with a diagnosis of acral lentiginous melanoma. A biopsy through the nail
performed elsewhere failed to confi rm the diagnosis. (B) Subungual melanoma: Correct
confi rmatory biopsy requires removal of the nail. The lesion involving the more proximal
nailbed germinal matrix is apparent.

MALIGNANT SKIN LESIONS • 73
Morpheaform (Sclerosing) BCC. A rare (2%–5%) but
aggressive variant that presents as a tan, white, or yellow-
ish atrophic plaque with ill-defi ned borders leading to dif-
fi culty in diagnosis and late presentation. Infl ammatory
induration is almost always present. The extent of the
tumor is usually not apparent on clinical examination, and
the surgical specimen frequently has involved margins. The
growth pattern is primarily radial, and ulceration remains
infrequent.
Pigmented BCC. A rare subtype (6%) that may be con-
fused with melanoma. The pigment is melanin and can
render the lesion a variety of colors ranging from tan to
black.
Squamous Cell Carcinoma. SCC is the second most
common skin cancer after BCC and usually is preceded
by sun damage, leukoplakia, actinic keratoses, or radiation
damage. Varying degrees of keratinocyte dysplasia iden-
tifi es SCC; keratin pearls and intercellular bridging are
seen on histologic examination. The grade of the tumor is
determined by the degree of cellular differentiation, with
high-grade tumors marked by increased cellular atypia and
loss of keratinization. SCC typically presents as a painless,
erythematous, poorly defi ned lesion with elevated borders;
they may resemble an actinic keratosis. Compared with
BCC, these tumors are more aggressive and nodal metasta-
ses occur at greater frequency.
SCC can be associated with long-standing wounds, irri-
tation, or infl ammation. Long-standing wounds have a 2%
risk of harboring an SCC. Originally described in the setting
of burn wounds (Marjolin ulcer), malignant degeneration
may occur in any chronic wound, including venous stasis
ulcers, decubitus ulcers, hidradenitis, and chronic osteo-
myelitis. Wound or scar-associated SCC is generally more
aggressive than its UV-induced counterpart and metasta-
sizes more frequently (20%–30%). The overall prognosis
for patients with metastatic disease is dismal. Of patients
with squamous cell carcinoma, 30% will develop an addi-
tional SCC after 5 years and more than 50% will develop
an additional nonmelanoma skin cancer. For SCC, the dif-
ferential includes squamous cell carcinoma, keratoacan-
thoma, eczema and atopic dermatitis, contact dermatitis,
psoriasis, pseudoepitheliomatous hyperplasia, bowenoid
papulosis, and seborrheic dermatitis.
Bowen’s Disease. A SCC in situ with epidermal and
follicular involvement. Only 10% of cases become locally
invasive; the rest remain localized for long periods.
Verrucous Carcinoma. A well-differentiated variant of
SCC so named due to its wart-like appearance. Local inva-
sion is common. Underlying bone involvement may occur;
however, metastases are rare. Involvement of the palmar
and plantar skin is common.
Merkel Cell Carcinoma. Merkel cell carcinoma (MCC)
an uncommon but highly aggressive primary malignant
tumor of the skin. It is often classifi ed as a neuroendocrine
tumor and the pathologic diagnosis may be diffi cult. MCC
is a rare tumor; therefore, limited prospective, statisti-
cally signifi cant data are available to verify or validity of
any prognostic features or treatment outcomes. Treatment
generally includes wide local excision with consideration
for sentinel node mapping and biopsy. Staging includes
a metastatic imaging evaluation. Referral to medical and
radiation oncology for discussion about adjuvant thereapy
is appropriate. Several large reviews document the devel-
opment of local recurrence in 25% to 33% of all cases of
MCC, regional disease in 25% of all cases, and distant met-
astatic disease in 33% of cases. The overall 5-year survival
rates range from 30% to 64%. MCC usually presents after
the sixth decade as a solitary nodule on a sun-exposed area
(up to 75% in the head and neck area).
Dermatofi brosarcoma Protuberans (DFSP). Dermato-
fi brosarcoma protuberans is a rare fi brohistiocytic sarcoma
that manifests clinically as a distinctive, raised, hard lesion
that begins as a plaque or small nodule. Most patients are
20 to 40 years old. DFPS is uncommon, low-grade sarcoma
and the incidence rate of 0.8 cases/million-persons/year.
The local recurrence rate for DFSP in studies ranges from
0% to 60%, whereas the rate of development of regional or
distant metastatic disease is only 1% and 4% to 5%, respec-
tively. Tumor characteristics include long, irregular, subclin-
ical extensions. Delayed reconstruction may be advisable
pending confi rmation of clear margins. The treatment is
wide local excision. The tumor has a propensity for sub-
clinical deep invasion, and deep resection is appropriate.
PATIENT PREPARATION
Patient preparation begins preoperatively with counsel-
ing regarding the need for complete tumor removal in
order to gain local control of disease. Cosmetic concerns
must be factored into the surgical plan, but they should
not limit the degree of resection required to obtain clear
and adequate surgical margins. Patients should be prepared
for the possibility of positive margins and the need for re-
excision. Perhaps, more importantly, the surgeon should
also be prepared, and a complex postablative reconstruc-
tion should be staged if there is any concern about resec-
tion margins. Realistic goals and expectations must be set
and thoroughly explained to the patient. The indications
for staging should be discussed, especially the potential
role for sentinel node mapping and biopsy in patients hav-
ing melanoma or Merkel cell carcinoma. Imaging studies
for patients at risk for metastatic disease should be ordered
and reviewed. The results may obviously impact the antici-
pated surgical plans in the event that metastatic disease
is evident. General anesthesia is appropriate for larger
procedures, but many resections can be performed with
only local. Patients should be positioned to allow access
to the entire tumor area and any potential fl ap donor sites
needed for reconstruction. Sterile technique is vital, as the
potential for infection remains high. Essential equipment

74 • CHAPTER 7
will vary, depending on the surgeon and procedure. In gen-
eral, electrocautery and bolster dressing supplies should be
available for all excisions.
SURGICAL TREATMENTS
Management of Melanoma
Currently, surgery is the only acceptable therapy for pri-
mary melanoma. Surgical resection of the primary involves
an en bloc resection with a surrounding margin of normal
skin and underlying soft tissue. The need for wide margins
was recognized by Handley in 1907, who recognized that
growth of the primary was discontinuous and that narrow
margins of resection while seeming complete would fail
to remove the subclinical spread along dermal lymphatics
and result in local recurrence. 8 The exact margins of resec-
tion remain a subject of much debate and consensus recom-
mendations exist ( Table 7-2 ). 9 Attempts to move toward
thinner margins in the context of clinical trials are met
with an increasing risk of local recurrence. Unfortunately,
local recurrence portends a poor prognosis. The goals of
surgical treatment are to provide local disease control for
all patients, even when the risk of systemic spread is high,
and to achieve a high cure in patients with early stage dis-
ease. Surgical practice calls for these goals to be met with-
out compromise, but also with consideration of functional
impairment and cosmetic disfi gurement Understanding the
relationship between surgical margins, local recurrences,
regional failures, and survival has motivated a standardiza-
tion of surgical melanoma care and, while the consensus
margin recommendations are not sacrosanct, they still
bear medicolegal importance and should be modifi ed only
if there are signifi cant functional or cosmetic concerns. In
addition to the radial surgical margins, questions regarding
the depth of excision have been addressed. It is currently
accepted that the excision need not include the underly-
ing fascia but should extend down to but not including the
muscle fascia. Patients having subungual melanoma (acral
lentiginous type) are managed with distal amputation of
the involved digit (usually at the distal interphalangeal
level).
Mohs micrographic surgery, a technique primarily used
by dermatologists, employs intraoperative margin assess-
ment to map the histologic extent of a malignant lesion,
allowing excision with a minimal surgical margin and
maximizing preservation of uninvolved tissue. The effi cacy
TABLE 7-2. Recommended Margins of
Excision for Melanoma
Thickness
Excision Margins
In situ
5 mm
,1 mm
1 cm
.1 mm
2 cm
.4 mm
2 cm at least
FIGURE 7-6. Lymphoscintigram: The study
demonstrates the unilateral axillary drainage pattern of
a midline melanoma of the back. Drainage patterns of
midline lesions are highly variable and lymphoscintigraphy
is a necessary component of the sentinel node mapping
procedure.
of this approach is well established for the management
of basal cell and squamous cell carcinoma (see below);
however, no prospective randomized clinical trials com-
paring Mohs techniques and standard surgical excisions
have been undertaken to date, and this technique is not
considered standard of care for the management of pri-
mary melanoma. Evaluation and management of regional
lymphatic involvement of melanoma is essential for both
cancer staging and patient survival. Once there is regional
spread of melanoma, prognostic factors related to the pri-
mary lesion (Breslow thickness, ulceration, histology, site,
number of mitoses) contribute very little to the overall
prognostic outlook. The status of the sentinel node is the
single most important prognostic factor for a patient hav-
ing melanoma. 10 Nodal metastases alone decrease 5-year
survival by roughly 40%. The sentinel lymph node (SLN)
is defi ned as the fi rst node (or nodes), within the chain
or network of nodes comprising the lymphatic basin, to
receive drainage form the primary tumor. The SLN is
therefore at highest risk of developing melanoma metasta-
ses. The histology of the SLN accurately refl ects the histol-
ogy of the entire of the basin. It was recognized only fairly
recently (mid 1990s) that lymphatic drainage is dynamic
and unpredictable. The correct preoperative identifi ca-
tion of the sentinel node and by defi nition the appropriate
nodal basin requires a lymphoscintigram usually per-
formed with Tc 99m–labeled sulfur colloid ( Figure 7-6 ).
The sentinel node mapping and biopsy procedure is best
performed at the time of defi nitive surgical management
of the primary. Lymphoscintigraphy is obtained prior to
surgery, usually several hours preoperatively. The primary
site is injected intradermally with vital blue dye (Isosulfan
Blue seems to be best) ( Figure 7-7 ). An intradermal injec-
tion is critical, and a subcutaneous injection may identify

MALIGNANT SKIN LESIONS • 75
the wrong node. The draining nodal basin is explored
using the blue dye as well as a handheld gamma probe
( Figure 7-8 ). The combination of both the blue dye and
the radiocolloid increase both the accuracy and ease of the
procedure. The sentinel node(s) are removed and submit-
ted for pathological review ( Figure 7-9 ). The pathologi-
cal review should include multiple-step sections and the
use of immunohistochemistry, both of which increase the
accuracy of the subsequent staging. The exact indications
for sentinel node mapping and biopsy remain a source of
controversy; however, it is generally accepted that patients
having a primary lesion of Breslow depth 1 to 4 mm are
appropriate candidates. Patients with thin lesions (,1 mm)
having additional poor prognostic signs such as ulceration
or Clark’s level IV are at higher risk for having nodal dis-
ease and therefore reasonably staged with sentinel node
mapping and biopsy.
FIGURE 7-7. Intradermal injection: Vital blue dye
(Isosulfan Blue) is injected into the primary site (primary
removed as an excisional biopsy) in preparation for operative
identifi cation of the sentinel node.
Management of Nonmelanoma Skin Cancer
Nonmelanoma skin cancers include Merkel cell carcinoma,
for which wide excision with margins comparable to the
recommendations for melanoma as above. Sentinel node
mapping and biopsy is evolving as an appropriate staging
procedure for MCC. DFSP tumors should also be widely
excised to fascia. Nodal disease is uncommon and there-
fore sentinel node biopsy (SNB) is not usually performed.
Treatment options for squamous cell and basal cell carci-
nomas include surgical excision, curettage and electrodes-
sication, cryosurgery, fractionated radiotherapy, topical
chemotherapy or immunotherapy (5-fl uorouracil, imiqui-
mod), carbon dioxide laser, photodynamic therapy, intral-
esional interferon, and retinoids. Laser treatment offers
theoretical advantages for certain patients, such as those
taking anticoagulants. However, primary excision remains
the most common treatment for BCC and SCC. Cure
rates can approach 99% when surgical margins are nega-
tive. Recurrent NMSC is diffi cult to manage having only a
50% cure rate. Mohs micrographic surgery is a reasonable
option for the management of the recurrent BCC. When
planning the excision, the size of the tumor, the clinical
type, grade, depth of invasion, the location, the ramifi ca-
tions of local recurrence, and patient factors (age, general
health, aesthetic considerations, etc) should be taken into
consideration.
The appropriate margin of resection for BCC is not
set in stone; rather, the surgeon must balance the risk
of recurrence with loss of function or diminished cos-
mesis. Excision with 5-mm margins has been recom-
mended by numerous authors as a general guideline,
although large lesions may require wider margins because
FIGURE 7-8. Intraoperative sentinel node identifi cation.
Lymphatics containing blue dye and identifying the sentinel
node are apparent.
FIGURE 7-9. Sentinel node: The sentinel node
containing blue dye and radiocolloid is removed and
submitted for pathological assessment.

76 • CHAPTER 7
margin positivity and recurrence rates increase with size.
Excisions of recurrent BCC are challenging because of
the high failure rates. Recurrence rates are highest in the
head and neck, especially the nose, and recurrent tumors
may be managed with Mohs micrographic surgery.
Reconstruction of the postablative defect may require
the use of local skin fl aps as described in Chapter 2
( Figure 7-10A,B ).
Defi nitive surgical margins for the management of SCC
are also unclear and dependent on tumor and host char-
acteristics. For lesions smaller than 2 cm, a 4-mm mar-
gin is likely adequate; whereas lesions larger than 2 cm
may be better managed with a 1-cm margin. The size of
the margins may be modifi ed depending on the differen-
tiation, size, and the invasion of surrounding structures.
Some authors advocate wider margins (3.5 cm margin for
a .3 cm tumor) to achieve a 95% cure rate. For high-risk
SCC, the margin should be 6 mm and the excision should
be into the subcutaneous fat. Early re-excision is recom-
mended in the event of positive resection margins. SNB is
not usually performed, although may be justifi ed in cases
where subclinical disease is likely based on either patient
or lesion risk factors.
Management of Nodal Disease. Patients having doc-
umented nodal disease are managed with completion
lympadenectomy and/or radiotherapy and should be
evaluated by medical oncology for adjuvant systemic
therapy.
POSTABLATIVE RECONSTRUCTION
Ideally, the resection is planned as an ellipse with the long
axis pointing toward the draining nodal basin or coincident
with lines of relaxed skin tension (cosmesis). The smaller
defects are closed primarily over a suction drain as needed.
Despite current evidence-based guidelines refl ecting a
A
B
FIGURE 7-10. (A) Postablative defect: A typical postablative defect following
surgical removal of a basal cell carcinoma. Defi nitive reconstruction in this case was
staged to allow confi rmation of clear margins. (B) Flap reconstruction: The postablative
defect is readily reconstructed with a banner-type transposition fl ap.
FIGURE 7-11. Skin graft reconstruction: The patient
underwent skin graft reconstruction of a postablative (basal
cell carcinoma excision) nasal defect elsewhere. The contour
deformity is apparent. While this approach is reasonable and
appropriate, a better cosmetic result may be obtained with a
local fl ap reconstruction.

MALIGNANT SKIN LESIONS • 77
trend toward conservatism, surgical excision often results
in a defect that cannot be closed primarily. As noted above,
if there is doubt that the primary has been resected with
clear margins, defi nitive reconstruction should be staged
pending pathologic confi rmation of clear margins. Care
should be taken to avoid any cross-contamination between
the ablative fi elds and fl ap or skin graft donor sites, as cuta-
neous malignancies can be transplanted. Primary closure
is often complicated after resections involving the distal
extremities, face, and scalp. For these defects, either split- or
full-thickness skin grafts are reasonable options for cover-
age. The shortcomings of skin grafting include suboptimal
cosmetic results, donor site morbidity, and the necessity
for patient immobilization postoperatively ( Figure 7-11 ).
Local fl aps, when appropriate and feasible, offer superior
cosmetic results and earlier patient mobility. In our experi-
ence, use of the versatile rhomboid fl ap, or rotation fl aps
have been valuable when primary closure is not feasible
or cosmetically acceptable (see Chapter 2). Rarely, more
sophisticated reconstructive techniques such as pedicled
fl aps or free fl aps may be required. Flap closure of mela-
noma excision defects is not associated with increased
local recurrence rates.
TABLE 7-3. TNM Staging Categories for Melanoma
T Classifi cation
Thickness (mm)
Ulceration Status/Mitoses
Tis
N/A
N/A
T1
#1.00
a: Without ulceration and mitosis , 1/mm 2
b: With ulceration and mitosis $ 1/mm 2
T2
1.01–2.00
a: Without ulceration
b: With ulceration
T3
2.01–4.00
a: Without ulceration
b: With ulceration
T4
.4.00
a: Without ulceration
b: With ulceration
N Classifi cation
No. of Metastatic Nodes
Nodal Metastatic Burden
N0
0
N/A
N1
1
a: Micrometastasis
b: Macrometastasis
N2
2–3
a: Micrometastasis
b: Macrometastasis
c: In transit metastases/satellites without
metastatic nodes
N3
41 metastatic nodes, or matted nodes, or in transit
metastases/satellites with metastatic nodes
M Classifi cation
Site
Serum LDH
M0
No distant metastases
N/A
M1a
Distant skin, subcutaneous, or nodal metastases
Normal
M1b
Lung metastases
Normal
M1c
All other visceral metastases
Normal
Any distant metastases
Elevated
LDH, lactate dehydrogenase; M, metastasis; N/A, not available; N, nodes; T, tumor.
Micrometastases are detected after sentinel lymph node biopsy.
COMPLICATIONS
Wound complications following primary resection occur
with a frequency that is related to the size and location of
the defect and include infections, dehiscence and hema-
toma, or seroma formation. Seroma formation may be
expected with a 30% incidence after SNB. Management
options include aspiration and formal incision and drainage.
Local-regional recurrences may occur with an incidence
that is proportional to the thickness of the primary but
may also refl ect inadequate management of the primary
lesion. Recurrences are managed with re-excision usually
with the more conservative 1-cm margin.
OUTCOMES ASSESSMENT
Staging for Melanoma
The staging of melanoma is important to practitioners, as it
provides a precise nomenclature for description of lesions
based on prognosis, a reliable system of patient stratifi ca-
tion in terms of risk of metastasis and survival rates, and
a consistent tool for judicious clinical decision making.
It is likewise important to researchers, as it permits fair

78 • CHAPTER 7
comparison of different treatment regimens and simplifi es
inclusion criteria for clinical trials. The staging of cutane-
ous melanoma has undergone many changes and modifi -
cations over the years based on ongoing research aimed
at determining the relationship between gross and histo-
pathologic characteristics and clinical behavior of the dis-
ease. Late in 2009, a multidisciplinary Melanoma Staging
Committee of the American Joint Committee on Cancer
met to revise the existing system of TNM classifi cation
and staging to refl ect the expanding understanding of the
disease 11 ( Tables 7-3 and 7-4 ). Important changes include:
(1) mitotic rate is now a criterion for defi ning T1b mela-
nomas; (2) in patients with distant metastases, the site of
metastases and LDH level defi ne the M category; (3) all
patients with microscopic metastases are now classifi ed as
stage III. In short, melanoma staging is based on anatomic
compartmentalization and categorizes patients with local-
ized melanoma into stages I/II, those with regional skin,
subcutaneous or nodal metastases to stage III, and those
with distant metastases to stage IV.
1. Mihm MC Jr, Sober AJ. Melanoma before and after Thomas
B. Fitzpatrick. J Invest Dermatol . 2004;122:32–33.
2. Ford D, Bliss JM, Swerdlow AJ, et al. Risk of cutaneous
melanoma associated with a family history of the disease.
The International Melanoma Analysis Group (IMAGE). Int
J Cancer . 1995;62:377–381.
3. Weinstock MA. Death from skin cancer among the elderly: epi-
demiological patterns. Arch Dermatol. 1997;133:1207–1209.
4. Elwood JM, Jopson J. Melanoma and sun exposure: an over-
view of published studies. Int J Cancer . 1997;73:198–203.
5. Tucker MA, Halpern A, Holly EA, et al. Clinically recog-
nized dysplastic nevi. A central risk factor for cutaneous
melanoma. JAMA . 1997;277:1439–1444.
6. Ford D, Bliss JM, Swerdlow AJ, et al. A. Risk of cutaneous
melanoma associated with a family history of the disease.
The International Melanoma Analysis Group (IMAGE). Int
J Cancer. 1995;62:377–381.
7. Carucci JA. Treatment of lentigo maligna. Cutis . 2001;67:
389–392.
8. Handley WS. The pathology of melanotic growths in relation
to their operative treatment. Lancet . 1907;1:927–933.
9. Lens MB, Nathan P, Bataille V. Excision margins for primary
cutaneous melanoma. Arch Surg . 2007;142(9):885–891.
10. Gershenwald JE, Thompson W, Mansfi eld PF, et al. Multi-
institutional melanoma lymphatic mapping experience: the
prognostic value of sentinel lymph node status in 612 stage
I or II melanoma patients. J Clin Oncol . 1999;17:976–983.
11. Balch CM, Gershenwald JE, Soong S, et al. Final version
of 2009 AJCC melanoma staging and classifi cation. J Clin
Oncol . 2009;27(36):6199–6206.
TABLE 7-4. Anatomic Stage Groupings for Melanoma
Clinical Staging
Pathologic Staging
T
N
M
T
N
M
0
Tis
N0
M0
0
Tis
N0
M0
IA
T1a
N0
M0
IA
T1a
N0
M0
IB
T1b
N0
M0
IB
T1b
N0
M0
T2a
N0
M0
T2a
N0
M0
IIA
T2b
N0
M0
IIA
T2b
N0
M0
T3a
N0
M0
T3a
N0
M0
IIB
T3b
N0
M0
IIB
T3b
N0
M0
T4a
N0
M0
T4a
N0
M0
IIC
T4b
N0
M0
IIC
T4b
N0
M0
III
Any T
N.N0
M0
IIIA
T1-4a
N1a
M0
T1-4a
N2b
M0
IIIB
T1-4b
N1a
M0
T1-4b
N2a
M0
T1-4a
N1b
M0
T1-4a
N2b
M0
T1-4a
N2c
M0
IIC
T1-4b
N1b
M0
T1-4b
N2b
M0
T1-4b
N2c
M0
Any T
N3
M0
IV
Any T
Any N
M1
IV
Any T
Any N
M1
M, metastasis; N, nodes; T, tumor.
REFERENCES

INTRODUCTION
Hemangiomas are the most common vascular anomaly of
infancy, occurring in 10% of full-term infants, but parents
can be largely reassured that all hemangiomas will pass
from a proliferative to an involutional phase, and up to
70% of hemangiomas will not require any specifi c inter-
ventional therapy. Chapter 9 addresses treatment options
for problematic hemangiomas.
Vascular malformations represent the remaining anoma-
lies, and it is important to distinguish these conditions from
hemangiomas, as the clinical course and treatment options
can be signifi cantly different. Unlike hemangiomas, the vast
majority of vascular malformations do not have the ability
to involute. Medicolegal situations can arise if parents are
advised to wait for slow regression that, in fact, will never
occur. Some conditions such as port wine stains warrant
immediate therapy beginning in infancy. This chapter will
address the most common vascular anomalies and outline
their clinical characteristics, diagnostic studies, and treat-
ment options.
PATIENT EVALUATION AND SELECTION
Vascular Malformations—
General Considerations
Vascular malformations represent structurally abnormal
vessels, predominantly due to abnormal in utero develop-
ment, but also infl uenced by actinic, hormonal, or gravita-
tional infl uence. Any type of vessel can be involved, and
the malformations are classifi ed by the type or types of
vessels involved. These include:
Capillary vascular malformations (port wine stains)
Venous malformations (including blue rubber bleb
nevus syndrome and glomus tumors)
Lymphatic malformations
Venolymphatic malformations
Arterial and arteriovenous malformations
Capillary, venous, and lymphatic malformations
(Klippel-Trenaunay syndrome)
Capillary and arteriovenous malformations
(Parkes-Weber syndrome)
Small collections of abnormal dermal vessels have his-
torically been given descriptive names, some of which are
not entirely accurate but have persisted through wide-
spread usage:
Pyogenic granulomas (lobular capillary hemangiomas)
Adenoma sebaceum (angiofi bromas)
Broken blood vessels (telangiectasias)
Spider angiomas
Spider veins
Cherry angiomas
Many of these conditions are also treated by dermatolo-
gists, and it is useful to develop a good working relation-
ship with these specialists, as they are the major referral
source of patients with vascular conditions needing surgi-
cal intervention.
Nonsurgical Therapy
for Vascular Malformations
Some vascular malformations are best treated by nonsurgi-
cal methods. Decongestive massage and compression wrap-
ping by rehabilitation medicine specialists, compression
garments, and compression pumps are often the treatment
of choice for lower extremity malformations characterized
by venous engorgement and lymphedema.
Sclerotherapy by an interventional radiologist is an
extremely useful option for many venous, lymphatic,
and venolymphatic malformations. This will often avoid
the need for surgical excision, or at least decrease the
8
Vascular Malformations
David W. Low, MD / M. Renee Jespersen, MD
c h a p t e r

80 • CHAPTER 8
risk of intraoperative bleeding. Sclerosing agents such as
absolute alcohol, doxycycline, sodium tetradecyl sulfate
(Sotradecol) injected under fl uoroscopic or ultrasonic
guidance can be used for subcutaneous or deeper subfascial
and intramuscular malformations. Plastics surgeons may
also perform sclerotherapy for superfi cial dermal vessels
using agents, such as hypertonic saline, sodium sotradecyl
sulfate, or recently FDA-approved polidocanol (Asclera).
30-gauge needles, 1 cc syringes, loupe magnifi cation, and
a steady hand are recommended for successful cannula-
tion of extremely tiny vessels. Post-treatment compression
with dental rolls or cotton balls and support stockings will
facilitate obliteration of spider and even (nonsaphenous)
varicose veins without the need for stripping and ligation.
Steroids and beta-blockers have no role in the treatment
of congenital vascular malformations, in contrast to heman-
giomas. Steroids and beta-blockers suppress endothelial
proliferation associated with hemangioma growth, but
have no ability to limit vascular dilatation and hypertrophy
associated with vascular malformations.
PATIENT PREPARATION
Laser Considerations
Lasers that target either oxyhemoglobin or water may be
useful in the palliative and occasionally curative treatment
of many vascular malformations. Although the continuous
beam Argon laser (blue-green light, 488 and 515 nm) was
the fi rst clinically useful laser for treating vascular condi-
tions, currently the pulsed yellow dye laser is the most
commonly used laser for a wide variety of dermal vascular
malformations. The organic rhodamine dye initially emit-
ted a pure yellow 577 nm wavelength, but succeeding gen-
erations of pulsed dye lasers have increased the wavelength
to 585 nm and currently 595 nm to achieve deeper dermal
penetration (Perfecta Vbeam). High-energy, short dura-
tion pulses of light tend to cause vascular disruption and
purpura rather than coagulation, and limit heat injury to
the vessels themselves. By respecting the “thermal relax-
ation time” of the vessels, pulsed lasers destroy vessels
with minimal damage to the surrounding dermis, a process
described as “selective photothermolysis.”
Continuous beam lasers that travel through fi beroptic
cables, such as the KTP and Nd:YAG lasers (Laserscope)
can achieve deeper coagulation through largely non-
specifi c heat transfer. These lasers may be more likely to
leave cutaneous scars, but may be more useful for bulky,
engorged vascular lesions such as venous malformations
and cherry angiomas. The fi bers can also be passed per-
cutaneously through large gauge hypodermic needles or
transmucosally to avoid excessive superfi cial thermal dam-
age ( Figure 8-1 ). Endovenous laser ablation is growing in
popularity as an alternative to venous stripping and liga-
tion for varicose veins, and it can also be used to treat other
venous malformations.
Carbon dioxide laser light is absorbed by water, mak-
ing them appropriate for vaporization or coagulation of a
FIGURE 8-1. Percutaneous deep laser photocoagulation
using a KTP laser fi ber and a hypodermic needle avoids
excessive heat damage to the epidermis.
variety of superfi cial vascular lesions such as lymphatic ves-
icles, angiokeratomas (crusted venolymphatic skin lesions),
and angiofi bromas (commonly called adenoma sebaceum, a
misnomer).
SURGICAL TREATMENT OF
VASCULAR MALFORMATIONS
Capillary Vascular Malformations
Capillary vascular malformation, commonly called port
wine stains, occur in 3 out of 1000 babies and can appear
anywhere on the body, but those on the face are obviously
the most distressing to parents. Often following a roughly
dermatomal distribution, capillary vascular malforma-
tion that include the V1 distribution of the head may also
involve ocular structures and the leptomeninges (Sturge-
Weber syndrome) ( Figure 8-2 ). These patients should be
routinely monitored for glaucoma, and parents should be
aware of the potential for seizures.
Pulsed yellow dye laser therapy is the treatment of
choice for capillary vascular malformations. Treatment
can begin in infancy, and depending upon the location of
the malformation, the discomfort of the laser pulses can
be reduced by a cryogen spray coupled to the laser hand-
piece, local anesthetic cream, fi eld block local anesthetic
injection (uncommon), or a general anesthetic (particu-
larly for facial port wine stains that involve the periorbital
area). Parents should be aware that although most capil-
lary vascular malformations will lighten with laser ther-
apy, virtually none will completely disappear. Also, lasers
characteristically leave purpuric spots for about 2 weeks,
followed by slow lightening of the vascular pigmentation
over 2 to 3 months. Most patients receive six to eight treat-
ments until a plateau in improvement is reached. Residual
pigmentation is presumably due to deep dermal vessels
that cannot be reached by the laser light. The neck and

VASCULAR MALFORMATIONS • 81
chest areas often lighten remarkably, the face lightens to
a variable degree, and hands and feet often show minimal
improvement ( Figure 8-3 ).
The goal of laser therapy is to lighten the vascular pig-
mentation as much as possible and also to try to avoid
hypertrophy of the capillaries and venules, which can lead
to deeper purple pigmentation, a raised nodular texture,
and sometimes signifi cant soft tissue hypertrophy and
distortion. Pediatric patients who have reached a plateau
in improvement may exhibit an increase in vascular pig-
mentation during their teenage and adult years due to
ongoing hypertrophy of the residual dermal vessels. Laser
therapy may again be effective in reducing the vascular
engorgement.
Macular stains, often called “stork bite” or “angel’s kiss,”
are pale pink patches that present in the midline glabella
and forehead and at the nape of the neck. Unlike port wine
stains, they have the inexplicable ability to fade spontane-
ously over the fi rst year of life, and therefore initial treat-
ment is conservative. Persistent macular stains virtually
disappear with 1 or 2 pulsed yellow dye laser treatments,
suggesting that these malformations are extremely super-
fi cial and easily obliterated by the laser light. Port wine
stains, in addition, may develop problematic bleeding
nodules and even pyogenic granulomas (lobular capillary
FIGURE 8-3. (A, B) Port wine stains of the neck and
chest respond extremely well to pulsed yellow dye laser
therapy. Signifi cant lightening is apparent after just one laser
treatment. Additional treatments may be given every 2 to
3 months until no further lightening is observed.
A
B
FIGURE 8-2. Capillary vascular malformations involving
the V1 distribution require monitoring for glaucoma and
seizure activity, clinical features of Sturge-Weber syndrome.
This patient has a prosthetic right eye.
hemangiomas) that usually are best treated by direct surgi-
cal excision.
Mid and lower facial capillary malformations (V2, V3
distribution) may also create signifi cant lip and cheek
hypertrophy. Lasers are not effective in retarding or reduc-
ing this bulk, and surgical removal of full-thickness verti-
cal wedges and transverse ellipses of vermilion and skin
are usually needed for adequate palliation ( Figure 8-4 ).
Temporary placement of noncrushing vascular clamps along
the commissures will help to reduce bleeding. Aggressive
debulking is analogous to surgical removal of a lip cancer,
and it may be necessary to remove one third to one half of
the lip to achieve adequate reduction ( Figure 8-5 ). Over-
correction may be desirable, as the residual involved tissue
will have a tendency to undergo additional hypertrophy.
Venous Malformations
Venous malformations range from small venous lakes to
extensive networks of dilated veins. They may be present at
birth or appear throughout life. They may be submucosal,